Nucleic acid encoding PRO229 polypeptides

ABSTRACT

The present invention is directed to novel polypeptides and to nucleic acid molecules encoding those polypeptides. Also provided herein are vectors and host cells comprising those nucleic acid sequences, chimeric polypeptide molecules comprising the polypeptides of the present invention fused to heterologous polypeptide sequences, antibodies which bind to the polypeptides of the present invention and to methods for producing the polypeptides of the present invention.

RELATED APPLICATIONS

This application is a continuation of, and claims priority under 35 USC§120 to, U.S. application Ser. No. 09/665,350 filed Sep. 18, 2000, whichis a continuation of and claims priority under 35 USC §120 to, PCTApplication PCT/US00/04414 filed Feb. 22, 2000, which is acontinuation-in-Part of and claims priority under 35 USC §120 to, PCTApplication PCT/US98/19330 filed Sep. 16, 1998, which claims priorityunder 35 USC §119 to U.S. Provisional Application 60/063,549 filed Oct.28, 1997.

FIELD OF THE INVENTION

The present invention relates generally to the identification andisolation of novel DNA and to the recombinant production of novelpolypeptides.

BACKGROUND OF THE INVENTION

Extracellular proteins play important roles in, among other things, theformation, differentiation and maintenance of multicellular organisms.The fate of many individual cells, e.g., proliferation, migration,differentiation, or interaction with other cells, is typically governedby information received from other cells and/or the immediateenvironment. This information is often transmitted by secretedpolypeptides (for instance, mitogenic factors, survival factors,cytotoxic factors, differentiation factors, neuropeptides, and hormones)which are, in turn, received and interpreted by diverse cell receptorsor membrane-bound proteins. These secreted polypeptides or signalingmolecules normally pass through the cellular secretory pathway to reachtheir site of action in the extracellular environment.

Secreted proteins have various industrial applications, including aspharmaceuticals, diagnostics, biosensors and bioreactors. Most proteindrugs available at present, such as thrombolytic agents, interferons,interleukins, erythropoietins, colony stimulating factors, and variousother cytokines, are secretory proteins. Their receptors, which aremembrane proteins, also have potential as therapeutic or diagnosticagents. Efforts are being undertaken by both industry and academia toidentify new, native secreted proteins. Many efforts are focused on thescreening of mammalian recombinant DNA libraries to identify the codingsequences for novel secreted proteins. Examples of screening methods andtechniques are described in the literature [see, for example, Klein etal., Proc. Natl. Acad. Sci. 93:7108-7113 (1996); U.S. Pat. No.5,536,637)].

Membrane-bound proteins and receptors can play important roles in, amongother things, the formation, differentiation and maintenance ofmulticellular organisms. The fate of many individual cells, e.g.,proliferation, migration, differentiation, or interaction with othercells, is typically governed by information received from other cellsand/or the immediate environment. This information is often transmittedby secreted polypeptides (for instance, mitogenic factors, survivalfactors, cytotoxic factors, differentiation factors, neuropeptides, andhormones) which are, in turn, received and interpreted by diverse cellreceptors or membrane-bound proteins. Such membrane-bound proteins andcell receptors include, but are not limited to, cytokine receptors,receptor kinases, receptor phosphatases, receptors involved in cell-cellinteractions, and cellular adhesin molecules like selectins andintegrins. For instance, transduction of signals that regulate cellgrowth and differentiation is regulated in part by phosphorylation ofvarious cellular proteins. Protein tyrosine kinases, enzymes thatcatalyze that process, can also act as growth factor receptors. Examplesinclude fibroblast growth factor receptor and nerve growth factorreceptor.

Membrane-bound proteins and receptor molecules have various industrialapplications, including as pharmaceutical and diagnostic agents.Receptor immunoadhesins, for instance, can be employed as therapeuticagents to block receptor-ligand interactions. The membrane-boundproteins can also be employed for screening of potential peptide orsmall molecule inhibitors of the relevant receptor/ligand interaction.

Efforts are being undertaken by both industry and academia to identifynew, native receptor or membrane-bound proteins. Many efforts arefocused on the screening of mammalian recombinant DNA libraries toidentify the coding sequences for novel receptor or membrane-boundproteins.

1. PRO211 and PRO217

Epidermal growth factor (EGF) is a conventional mitogenic factor thatstimulates the proliferation of various types of cells includingepithelial cells and fibroblasts. EGF binds to and activates the EGFreceptor (EGFR), which initiates intracellular signaling and subsequenteffects. The EGFR is expressed in neurons of the cerebral cortex,cerebellum, and hippocampus in addition to other regions of the centralnervous system (CNS). In addition, EGF is also expressed in variousregions of the CNS. Therefore, EGF acts not only on mitotic cells, butalso on postmitotic neurons. In fact, many studies have indicated thatEGF has neurotrophic or neuromodulatory effects on various types ofneurons in the CNS. For example, EGF acts directly on cultured cerebralcortical and cerebellar neurons, enhancing neurite outgrowth andsurvival. On the other hand, EGF also acts on other cell types,including septal cholinergic and mesencephalic dopaminergic neurons,indirectly through glial cells. Evidence of the effects of EGF onneurons in the CNS is accumulating, but the mechanisms of action remainessentially unknown. EGF-induced signaling in mitotic cells is betterunderstood than in postritotic neurons. Studies of clonedpheochromocytoma PC12 cells and cultured cerebral cortical neurons havesuggested that the EGF-induced neurotrophic actions are mediated bysustained activation of the EGFR and mitogen-activated protein kinase(MAPK) in response to EGF. The sustained intracellular signalingcorrelates with the decreased rate of EGFR down-regulation, which mightdetermine the response of neuronal cells to EGF. It is likely that EGFis a multi-potent growth factor that acts upon various types of cellsincluding mitotic cells and postmitotic neurons.

EGF is produced by the salivary and Brunner's glands of thegastrointestinal system, kidney, pancreas, thyroid gland, pituitarygland, and the nervous system, and is found in body fluids such assaliva, blood, cerebrospinal fluid (CSF), urine, amniotic fluid,prostatic fluid, pancreatic juice, and breast milk, Plata-Salaman,Peptides 12:653-663 (1991).

EGF is mediated by its membrane specific receptor, which contains anintrinsic tyrosine kinase. Stoscheck et al., J. Cell Biochem. 31:135-152 (1986). EGF is believed to function by binding to theextracellular portion of its receptor which induces a transmembranesignal that activates the intrinsic tyrosine kinase.

Purification and sequence analysis of the EGF-like domain has revealedthe presence of six conserved cysteine residues which cross-bind tocreate three peptide loops. Savage et al., J. Bio. Chem. 248: 7669-7672(1979). It is now generally known that several other peptides can reactwith the EGF receptor which share the same generalized motif. Nonisolated peptides having this motif include TGF-α, amphiregulin,schwannoma-derived growth factor (SDGF), heparin-binding EGF-like growthfactors and certain virally encoded peptides (e.g., Vaccinia virus,Reisner, Nature 313: 801-803 (1985), Shope fibroma virus, Chang et al.,Mol Cell Biol. 7: 535-540 (1987), Molluscum contagiosum, Porter andArchard, J. Gen. Virol. 68: 673-682 (1987), and Myxoma virus, Upton etal., J. Virol. 61: 1271-1275 (1987), Prigent and Lemoine, Prog. GrowthFactor Res. 4: 1-24 (1992).

EGF-like domains are not confined to growth factors but have beenobserved in a variety of cell-surface and extracellular proteins whichhave interesting properties in cell adhesion, protein-proteininteraction and development, Laurence and Gusterson, Tumor Biol.11:229-261 (1990). These proteins include blood coagulation factors(factors VI, IX, X, XII, protein C, protein S, protein Z, tissueplasminogen activator, urokinase), extracellular matrix components(laminin, cytotactin, entactin), cell surface receptors (LDL receptor,thrombomodulin receptor) and immunity-related proteins (complement C1r,uromodulin).

Even more interesting, the general structure pattern of EGF-likeprecursors is preserved through lower organisms as well as in mammaliancells. A number of genes with developmental significance have beenidentified in invertebrates with EGF-like repeats. For example, thenotch gene of Drosophila encodes 36 tandemly arranged 40 amino acidrepeats which show homology to EGF, Wharton et al., Cell 43: 557-581(1985). Hydropathy plots indicate a putative membrane spanning domain,with the EGF-related sequences being located on the extracellular sideof the membrane. Other homeotic genes with EGF-like repeats includeDelta, 95F and 5ZD which were identified using probes based on Notch,and the nematode gene Lin-12 which encodes a putative receptor for adevelopmental signal transmitted between two specified cells.

Specifically, EGF has been shown to have potential in the preservationand maintenance of gastrointestinal mucosa and the repair of acute andchronic mucosal lesions, Konturek et al., Eur. J. Gastroenterol Hepatol.7 (10), 933-37 (1995), including the treatment of necrotizingenterocolitis, Zollinger-Ellison syndrome, gastrointestinal ulcerationgastrointestinal ulcerations and congenital microvillus atrophy,Guglietta and Sullivan, Eur. J. Gastroenterol Hepatol, 7(10), 945-50(1995). Additionally, EGF has been implicated in hair follicledifferentiation; du Cros, J. Invest. Dermatol. 101 (1 Suppl.), 106S-113S(1993), Hillier, Clin. Endocinol. 33(4), 427-28 (1990); kidney function,Hamm et al., Semin. Nephrol. 13 (1): 109-15 (1993), Harris, Am. J.Kidney Dis. 17(6): 627-30 (1991); tear fluid, van Setten et al., Int.Ophthalmol 15(6); 359-62(1991); vitamin K mediated blood coagulation,Stenflo et al., Blood 78(7): 1637-51(1991). EGF is also implicatedvarious skin disease characterized by abnormal keratinocytedifferentiation, e.g., psoriasis, epithelial cancers such as squamouscell carcinomas of the lung, epidermoid carcinoma of the vulva andgliomas. King et al., Am. J. Med. Sci. 296:154-158 (1988).

Of great interest is mounting evidence that genetic alterations ingrowth factors signaling pathways are closely linked to developmentalabnormalities and to chronic diseases including cancer. Aaronson,Science 254:1146-1153 (1991). For example, c-erb-2 (also known asHER-2), a proto-oncogene with close structural similarity to EGFreceptor protein, is overexpressed in human breast cancer. King et al.,Science 229: 974-976 (1985); Gullick, Hormones and their actions, Cookeet al., eds, Amsterdam, Elsevier, pp 349-360 (1986).

We herein describe the identification and characterization of novelpolypeptides having homology to EGF, wherein those polypeptides areherein designated PRO211 and PRO217.

2. PRO230

Nephritis is a condition characterized by inflammation of the kidneyaffecting the structure and normal function of the kidney. Thiscondition can be chronic or acute and is generally caused by infection,degenerative process or vascular disease. In all cases, early detectionis desirable so that the patient with nephritis can begin treatment ofthe condition.

An approach to detecting nephritis is to determine the antigensassociated with nephritis and antibodies thereto. In rabbit, atubulointerstitial nephritis antigen (TIN-ag) has been reported inNelson, T. R., et al., J. Biol. Chem., 270(27):16265-70 (July 1995)(GENBANK/U24270). This study reports that the rabbit TIN-ag is abasement membrane glycoprotein having a predicted amino acid sequencewhich has a carboxyl-terminal region exhibiting 30% homology with humanpreprocathepsin B, a member of the cystein proteinase family ofproteins. It is also reported that the rabbit TIN-ag has a domain in theamino-terminal region containing an epidermal growth factor-like motifthat shares homology with laminin A and S chains, alpha 1 chain of typeI collagen, von Willebrand's factor and mucin, indicating structural andfunctional similarities. Studies have also been conducted in mice.However, it is desirable to identify tubulointerstitial nephritisantigens in humans to aid in the development of early detection methodsand treatment of nephritis.

Proteins which have homology to tubulointerstitial nephritis antigensare of particular interest to the medical and industrial communities.Often, proteins having homology to each other have similar function. Itis also of interest when proteins having homology do not have similarfunctions, indicating that certain structural motifs identifyinformation other than function, such as locality of function. We hereindescribe the identification and characterization of a novel polypeptide,designated hgerein as PRO230, which has homology to tubulointerstitialnephritis antigens.

3. PRO232

Stem cells are undifferentiated cells capable of (a) proliferation, (b)self maintenance, (c) the production of a large number of differentiatedfunctional progeny, (d) regeneration of tissue after injury and/or (e) aflexibility in the use of these options. Stem cells often express cellsurface antigens which are capable of serving as cell specific markersthat can be exploited to identify stem cells, thereby providing a meansfor identifying and isolating specific stem cell populations.

Having possession of different stem cell populations will allow for anumber of important applications. For example, possessing a specificstem cell population will allow for the identification of growth factorsand other proteins which are involved in their proliferation anddifferentiation. In addition, there may be as yet undiscovered proteinswhich are associated with (1) the early steps of dedication of the stemcell to a particular lineage, (2) prevention of such dedication, and (3)negative control of stem cell proliferation, all of which may beidentified if one has possession of the stem cell population. Moreover,stem cells are important and ideal targets for gene therapy where theinserted genes promote the health of the individual into whom the stemcells are transplanted. Finally, stem cells may play important roles intransplantation of organs or tissues, for example liver regeneration andskin grafting.

Given the importance of stem cells in various different applications,efforts are currently being undertaken by both industry and academia toidentify new, native stem cell antigen proteins so as to providespecific cell surface markers for identifying stem cell populations aswell as for providing insight into the functional roles played by stemcell antigens in cell proliferation and differentiation. We hereindescribe the identification and characterization of novel polypeptideshaving homology to a stem cell antigen, wherein those polypeptides areherein designated as PRO232 polypeptides.

4. PRO187

Growth factors are molecular signals or mediators that enhance cellgrowth or proliferation, alone or in concert, by binding to specificcell surface receptors. However, there are other cellular reactions thanonly growth upon expression to growth factors. As a result, growthfactors are better characterized as multifunctional and potent cellularregulators. Their biological effects include proliferation, chemotaxisand stimulation of extracellular matrix production. Growth factors canhave both stimulatory and inhibitory effects. For example, transforminggrowth factor (TGF-β) is highly pleiotropic and can stimulateproliferation in some cells, especially connective tissue, while being apotent inhibitor of proliferation in others, such as lymphocytes andepithelial cells.

The physiological effect of growth stimulation or inhibition by growthfactors depends upon the state of development and differentiation of thetarget tissue. The mechanism of local cellular regulation by classicalendocrine molecules involves comprehends autocrine (same cell),juxtacrine (neighbor cell), and paracrine (adjacent cells) pathways.Peptide growth factors are elements of a complex biological language,providing the basis for intercellular communication. They permit cellsto convey information between each other, mediate interaction betweencells and change gene expression. The effect of these multifunctionaland pluripotent factors is dependent on the presence or absence of otherpeptides.

FGF-8 is a member of the fibroblast growth factors (FGFs) which are afamily of heparin-binding, potent mitogens for both normal diploidfibroblasts and established cell lines, Gospodarowicz et al. (1984),Proc. Natl. Acad. Sci. USA 81:6963. The FGF family comprises acidic FGF(FGF-1), basic FGF (FGF-2), INT-2 (FGF-3), K-FGF/HST (FGF-4), FGF-5,FGF-6, KGF (FGF-7), AIGF (FGF-8) among others. All FGFs have twoconserved cysteine residues and share 30-50% sequence homology at theamino acid level. These factors are mitogenic for a wide variety ofnormal diploid mesoderm-derived and neural crest-derived cells,including granulosa cells, adrenal cortical cells, chondrocytes,myoblasts, corneal and vascular endothelial cells (bovine or human),vascular smooth muscle cells, lens, retina and prostatic epithelialcells, oligodendrocytes, astrocytes, chrondocytes, myoblasts andosteoblasts.

Fibroblast growth factors can also stimulate a large number of celltypes in a non-mitogenic manner. These activities include promotion ofcell migration into wound area (chemotaxis), initiation of new bloodvessel formulation (angiogenesis), modulation of nerve regeneration andsurvival (neurotrophism), modulation of endocrine functions, andstimulation or suppression of specific cellular protein expression,extracellular matrix production and cell survival. Baird & Bohlen,Handbook of Exp. Pharmacol. 95(1): 369-418, Springer, (1990). Theseproperties provide a basis for using fibroblast growth factors intherapeutic approaches to accelerate wound healing, nerve repair,collateral blood vessel formation, and the like. For example, fibroblastgrowth factors have been suggested to minimize myocardium damage inheart disease and surgery (U.S. Pat. No. 4,378,347).

FGF-8, also known as androgen-induced growth factor (AIGF), is a 215amino acid protein which shares 30-40% sequence homology with the othermembers of the FGF family. FGF-8 has been proposed to be underandrogenic regulation and induction in the mouse mammary carcinoma cellline SC3. Tanaka et al., Proc. Natl. Acad. Sci. USA 89: 8928-8932(1992); Sato et al., J. Steroid Biochem. Molec. Biol. 47: 91-98 (1993).As a result, FGF-8 may have a local role in the prostate, which is knownto be an androgen-responsive organ. FGF-8 can also be oncogenic, as itdisplays transforming activity when transfected into NIH-3T3fibroblasts. Kouhara et al., Oncogene 9 455-462 (1994). While FGF-8 hasbeen detected in heart, brain, lung, kidney, testis, prostate and ovary,expression was also detected in the absence of exogenous androgens.Schmitt et al., J. Steroid Biochem. Mol. Biol. 57 (3-4): 173-78 (1996).

FGF-8 shares the property with several other FGFs of being expressed ata variety of stages of murine embryogenesis, which supports the theorythat the various FGFs have multiple and perhaps coordinated roles indifferentiation and embryogenesis. Moreover, FGF-8 has also beenidentified as a protooncogene that cooperates with Wnt-1 in the processof mammary tumorigenesis (Shackleford et al., Proc. Natl. Acad. Sci. USA90, 740-744 (1993); Heikinheimo et al., Mech. Dev. 48: 129-138 (1994)).

In contrast to the other FGFs, FGF-8 exists as three protein isoforms,as a result of alternative splicing of the primary transcript. Tanaka etal., supra. Normal adult expression of FGF-8 is weak and confined togonadal tissue, however northern blot analysis has indicated that FGF-8mRNA is present from day 10 through day 12 or murine gestation, whichsuggests that FGF-8 is important to normal development. Heikinheimo etal., Mech Dev. 48(2): 129-38 (1994). Further in situ hybridizationassays between day 8 and 16 of gestation indicated initial expression inthe surface ectoderm of the first bronchial arches, the frontonasalprocess, the forebrain and the midbrain-hindbrain junction. At days10-12, FGF-8 was expressed in the surface ectoderm of the forelimb andhindlimb buds, the nasal its and nasopharynx, the infundibulum and inthe telencephalon, diencephalon and metencephalon. Expression continuesin the developing hindlimbs through day 13 of gestation, but isundetectable thereafter. The results suggest that FGF-8 has a uniquetemporal and spatial pattern in embryogenesis and suggests a role forthis growth factor in multiple regions of ectodermal differentiation inthe post-gastrulation embryo.

We herein describe the identification of novel poypeptides havinghomology to FGF-8, wherein those polypeptides are heein designatedPRO187 polypeptides.

5. PRO265

Protein-protein interactions include receptor and antigen complexes andsignaling mechanisms. As more is known about the structural andfunctional mechanisms underlying protein-protein interactions,protein-protein interactions can be more easily manipulated to regulatethe particular result of the protein-protein interaction. Thus, theunderlying mechanisms of protein-protein interactions are of interest tothe scientific and medical community.

All proteins containing leucine-rich repeats are thought to be involvedin protein-protein interactions. Leucine-rich repeats are short sequencemotifs present in a number of proteins with diverse functions andcellular locations. The crystal structure of ribonuclease inhibitorprotein has revealed that leucine-rich repeats correspond to beta-alphastructural units. These units are arranged so that they form a parallelbeta-sheet with one surface exposed to solvent, so that the proteinacquires an unusual, nonglubular shape. These two features have beenindicated as responsible for the protein-binding functions of proteinscontaining leucine-rich repeats. See, Kobe and Deisenhofer, TrendsBiochem. Sci., 19(10):415-421 (October 1994).

A study has been reported on leucine-rich proteoglycans which serve astissue organizers, orienting and ordering collagen fibrils duringontogeny and are involved in pathological processes such as woundhealing, tissue repair, and tumor stroma formation. Iozzo, R. V., Crit.Rev. Biochem. Mol. Biol., 32(2):141-174 (1997). Others studiesimplicating leucine rich proteins in wound healing and tissue repair areDe La Salle, C., et al., Vouv. Rev. Fr. Hematol. (Germany),37(4):215-222 (1995), reporting mutations in the leucine rich motif in acomplex associated with the bleeding disorder Bernard-Soulier syndromeand Chlemetson, K. J., Thromb. Haemost. (Germany), 74(1):111-116 (July1995), reporting that platelets have leucine rich repeats. Anotherprotein of particular interest which has been reported to haveleucine-rich repeats is the SLIT protein which has been reported to beuseful in treating neuro-degenerative diseases such as Alzheimer'sdisease, nerve damage such as in Parkinson's disease, and for diagnosisof cancer, see, Artavanistsakonas, S. and Rothberg, J. M., WO9210518-A1by Yale University. Other studies reporting on the biological functionsof proteins having leucine-rich repeats include: Tayar, N., et al., Mol.Cell Endocrinol., (Ireland), 125(1-2):65-70 (December 1996)(gonadotropin receptor involvement); Miura, Y., et al., Nippon Rinsho(Japan), 54(7): 1784-1789 (July 1996) (apoptosis involvement); Harris,P. C., et al., J. Am. Soc. Nephrol., 6(4):1125-1133 (October 1995)(kidney disease involvement); and Ruoslahti, E. I., et al., WO9110727-Aby La Jolla Cancer Research Foundation (decorin binding to transforminggrowth factor-β involvement for treatment for cancer, wound healing andscarring). Also of particular interest is fibromodulin and its use toprevent or reduce dermal scarring. A study of fibromodulin is found inU.S. Pat. No. 5,654,270 to Ruoslahti, et al.

Efforts are therefore being undertaken by both industry and academia toidentify new proteins having leucine rich repeats to better understandprotein-protein interactions. Of particular interest are those proteinshaving leucine rich repeats and homology to known proteins havingleucine rich repeats such as fibromodulin, the SLIT protein and plateletglycoprotein V. Many efforts are focused on the screening of mammalianrecombinant DNA libraries to identify the coding sequences for novelsecreted and membrane-bound proteins having leucine rich repeats. Weherein describe the identification and characterization of novelpolypeptides having homology to fibromodulin, herein designated asPRO265 polypeptides.

6. PRO219

Human matrilin-2 polypeptide is a member of the von Willebrand factortype A-like module superfamily. von Willebrand factor is a protein whichplays an important role in the maintenence of hemostasis. Morespecifically, von Willebrand factor is a protein which is known toparticipate in platelet-vessel wall interactions at the site of vascularinjury via its ability to interact and form a complex with Factor VIII.The absence of von Willebrand factor in the blood causes an abnormalitywith the blood platelets that prevents platelet adhesion to the vascularwall at the site of the vascular injury. The result is the propensityfor brusing, nose bleeds, intestinal bleeding, and the like comprisingvon Willebrand's disease.

Given the physiological importance of the blood clotting factors,efforts are currently being undertaken by both industry and academia toidentify new, native proteins which may be involved in the coagulationprocess. We herein describe the identification of a novel full-lengthpolypeptide which possesses homology to the human matrilin-2 precursorpolypeptide.

7. PRO246

The cell surface protein HCAR is a membrane-bound protein that acts as areceptor for subgroup C of the adenoviruses and subgroup B of thecoxsackieviruses. Thus, HCAR may provide a means for mediating viralinfection of cells in that the presence of the HCAR receptor on thecellular surface provides a binding site for viral particles, therebyfacilitating viral infection.

In light of the physiological importance of membrane-bound proteins andspecficially those which serve a cell surface receptor for viruses,efforts are currently being undertaken by both industry and academia toidentify new, native membrane-bound receptor proteins. Many of theseefforts are focused on the screening of mammalian recombinant DNAlibraries to identify the coding sequences for novel receptor proteins.We herein describe a novel membrane-bound polypeptide (designated hereinas PRO246) having homology to the cell surface protein HCAR and tovarious tumor antigens including A33 and carcinoembryonic antigen,wherein this polypeptide may be a novel cell surface virus receptor ortumor antigen.

8. PRO228

There are a number of known seven transmembrane proteins and within thisfamily is a group which includes CD97 and EMR1. CD97 is a seven-spantransmembrane receptor which has a cellular ligand, CD55, DAF. Hamann,et al., J. Exp. Med. (U.S.), 184(3):1189 (1996). Additionally, CD97 hasbeen reported as being a dedifferentiation marker in human thyroidcarcinomas and as associated with inflammation. Aust, et al., CancerRes. (U.S.), 57(9):1798 (1997); Gray, et al., J. Immunol. (U.S.),157(12):5438 (1996). CD97 has also been reported as being related to thesecretin receptor superfamily, but unlike known members of that family,CD97 and EMR1 have extended extracellular regions that possess severalEGF domains at the N-terminus. Hamann, et al., Genomics, 32(1):144(1996); Harmann, et al., J. Immunol., 155(4):1942 (1995). EMR1 isfurther described in Lin, et al., Genomics, 41(3):301 (1997) and Baud,et al., Genomics, 26(2):334 (1995). While CD97 and EMR1 appear to berelated to the secretin receptors, a known member of the secretin familyof G protein-coupled receptors includes the alpha-latroxin receptor,latrophilin, which has been described as calcium independent andabundant among neuronal tissues. Lelianova, et al., J. Biol. Chem.,272(34), 21504 (1997); Davletov, et al., J. Biol. Chem. (U.S.),271(38):23239 (1996). Both members of the secretin receptor superfamilyand non-members which are related to the secretin receptor superfamily,or CRF and calcitonin receptors are of interest. In particular, newmembers of these families, identified by their homology to knownproteins, are of interest.

Efforts are being undertaken by both industry and academia to identifynew membrane-bound receptor proteins, particularly transmembraneproteins with EGF repeats and large N-terminuses which may belong to thefamily of seven-transmembrane proteins of which CD97 and EMR1 aremembers. We herein describe the identification and charactization ofnovel polypeptides having homology to CD97 and EMR1, designated hereinas PRO228 polypeptides.

9. PRO533

Growth factors are molecular signals or mediators that enhance cellgrowth or proliferation, alone or in concert, by binding to specificcell surface receptors. however, there are other cellular reactions thanonly growth upon expression to growth factors. As a result, growthfactors are better characterized as multifunctional and potent cellularregulators. Their biological effects include proliferation, chemotaxisand stimulation of extracellular matrix production. Growth factors canhave both stimulatory and inhibitory effects. For example, transforminggrowth factors (TGF-β) is highly pleiotropic and can stimulateproliferation in some cells, especially connective tissues, while beinga potent inhibitor of proliferation in others, such as lymphocytes andepithelial cells.

The physiological effect of growth stimulation or inhibition by growthfactors depends upon the state of development and differentiation of thetarget tissue. The mechanism of local cellular regulation by classicalendocrine molecules comprehends autocrine (same cell), juxtacrine(neighbor cell), and paracrine (adjacent cell) pathways. Peptide growthfactors are elements of a complex biological language, providing thebasis for intercellular communication. They permit cells to conveyinformation between each other, mediate interaction between cells andchange gene expression. the effect of these multifunctional andpluripotent factors is dependent on the presence or absence of otherpeptides.

Fibroblast growth factors (FGFs) are a family of heparin-binding, potentmitogens for both normal diploid fibroblasts and established cell lines,Godpodarowicz, D. et al. (1984), Proc. Natl. Acad. Sci. USA 81: 6983.the FGF family comprises acidic FGF (FGF-1), basic FGF (FGF-2), INT-2(FGF-3), K-FGF/HST (FGF-4), FGF-5, FGF-6, KGF (FGF-7), AIGF (FGF-8)among others. All FGFs have two conserved cysteine residues and share30-50% sequence homology at the amino acid level. These factors aremitogenic for a wide variety of normal diploid mesoderm-derived andneural crest-derived cells, inducing granulosa cells, adrenal corticalcells, chrondocytes, myoblasts, corneal and vascular endothelial cells(bovine or human), vascular smooth muscle cells, lens, retina andprostatic epithelial cells, oligodendrocytes, astrocytes, chrondocytes,myoblasts and osteoblasts.

Fibroblast growth factors can also stimulate a large number of celltypes in a non-mitogenic manner. These activities include promotion ofcell migration into a wound area (chemotaxis), initiation of new bloodvessel formulation (angiogenesis), modulation of nerve regeneration andsurvival (neurotrophism), modulation of endocrine functions, andstimulation or suppression of specific cellular protein expression,extracellular matrix production and cell survival. Baird, A. & Bohlen,P., Handbook of Exp. Phrmacol. 95(1): 369-418 (1990). These propertiesprovide a basis for using fibroblast growth factors in therapeuticapproaches to accelerate wound healing, nerve repair, collateral bloodvessel formation, and the like. For example, fibroblast growth factors,have been suggested to minimize myocardium damage in heart disease andsurgery (U.S. Pat. No. 4,378,437).

We herein describe the identification and characterization of novelpolypeptides having homology to FGF, herein designated PRO533polypeptides.

10. PRO245

Some of the most important proteins involved in the above describedregulation and modulation of cellular processes are the enzymes whichregulate levels of protein phosphorylation in the cell. For example, itis known that the transduction of signals that regulate cell growth anddifferentiation is regulated at least in part by phosphorylation anddephosphorylation of various cellular proteins. The enzymes thatcatalyze these processes include the protein kinases, which function tophosphorylate various cellular proteins, and the protein phosphatases,which function to remove phosphate residues from various cellularproteins. The balance of the level of protein phosphorylation in thecell is thus mediated by the relative activities of these two types ofenzymes.

Although many protein kinase enzymes have been identified, thephysiological role played by many of these catalytic proteins has yet tobe elucidated. It is well known, however, that a number of the knownprotein kinases function to phosphorylate tyrosine residues in proteins,thereby leading to a variety of different effects. Perhaps mostimportantly, there has been a great deal of interest in the proteintyrosine kinases since the discovery that many oncogene products andgrowth factors possess intrinsic protein tyrosine kinase activity. Thereis, therefore, a desire to identify new members of the protein tyrosinekinase family.

Given the physiological importance of the protein kinases, efforts arebeing undertaken by both industry and academia to identify new, nativekinase proteins. Many of these efforts are focused on the screening ofmammalian recombinant DNA libraries to identify the coding sequences fornovel kinase proteins. We herein describe the identification andcharacterization of novel polypeptides having homology to tyrosinekinase g proteins, designated herein as PRO245 polypeptides.

11. PRO220, PRO221 and PRO227

Protein-protein interactions include receptor and antigen complexes andsignaling mechanisms. As more is known about the structural andfunctional mechanisms underlying protein-protein interactions,protein-protein interactions can be more easily manipulated to regulatethe particular result of the protein-protein interaction. Thus, theunderlying mechanisms of protein-protein interactions are of interest tothe scientific and medical community.

All proteins containing leucine-rich repeats are thought to be involvedin protein-protein interactions. Leucine-rich repeats are short sequencemotifs present in a number of proteins with diverse functions andcellular locations. The crystal structure of ribonuclease inhibitorprotein has revealed that leucine-rich repeats correspond to beta-alphastructural units. These units are arranged so that they form a parallelbeta-sheet with one surface exposed to solvent, so that the proteinacquires an unusual, nonglubular shape. These two features have beenindicated as responsible for the protein-binding functions of proteinscontaining leucine-rich repeats. See, Kobe and Deisenhofer, TrendsBiochem. Sci., 19(10):415-421 (October 1994).

A study has been reported on leucine-rich proteoglycans which serve astissue organizers, orienting and ordering collagen fibrils duringontogeny and are involved in pathological processes such as woundhealing, tissue repair, and tumor stroma formation. Iozzo, R. V., Crit.Rev. Biochem. Mol. Biol., 32(2):141-174 (1997). Others studiesimplicating leucine rich proteins in wound healing and tissue repair areDe La Salle, C., et al., Vouv. Rev. Fr. Hematol. (Germany),37(4):215-222 (1995), reporting mutations in the leucine rich motif in acomplex associated with the bleeding disorder Bernard-Soulier syndromeand Chlemetson, K. J., Thromb. Haemost. (Germany), 74(1):111-116 (July1995), reporting that platelets have leucine rich repeats. Anotherprotein of particular interest which has been reported to haveleucine-rich repeats is the SLIT protein which has been reported to beuseful in treating neuro-degenerative diseases such as Alzheimer'sdisease, nerve damage such as in Parkinson's disease, and for diagnosisof cancer, see, Artavanistsakonas, S. and Rothberg, J. M., WO9210518-A1by Yale University. Other studies reporting on the biological functionsof proteins having leucine-rich repeats include: Tayar, N., et al., Mol.Cell Endocrinol., (Ireland), 125(1-2):65-70 (December 1996)(gonadotropin receptor involvement); Miura, Y., et al., Nippon Rinsho(Japan), 54(7): 1784-1789 (July 1996) (apoptosis involvement); Harris,P. C., et al., J. Am. Soc. Nephrol., 6(4):1125-1133 (October 1995)(kidney disease involvement); and Ruoslahti, E. I., et al., WO9110727-Aby La Jolla Cancer Research Foundation (decorin binding to transforminggrowth factorβ involvement for treatment for cancer, wound healing andscarring).

Efforts are therefore being undertaken by both industry and academia toidentify new proteins having leucine rich repeats to better understandprotein-protein interactions. Of particular interest are those proteinshaving leucine rich repeats and homology to known proteins havingleucine rich repeats such as the SLIT protein and platelet glycoproteinV.

12. PRO258

Immunoglobulins are antibody molecules, the proteins that function bothas receptors for antigen on the B-cell membrane and as the secretedproducts of the plasma cell. Like all antibody molecules,immunoglobulins perform two major functions: they bind specifically toan antigen and they participate in a limited number of biologicaleffector functions. Therefore, new members of the Ig superfamily arealways of interest. Molecules which act as receptors by various virusesand those which act to regulate immune function are of particularinterest. Also of particular interest are those molecules which havehomology to known Ig family members which act as virus receptors orregulate immune function. Thus, molecules having homology to poliovirusreceptors, CRTAM and CD166 (a ligand for lymphocyte antigen CD6) are ofparticular interest.

Extracellular and membrane-bound proteins play important roles in theformation, differentiation and maintenance of multicellular organisms.The fate of many individual cells, e.g., proliferation, migration,differentiation, or interaction with other cells, is typically governedby information received from other cells and/or the immediateenvironment. This information is often transmitted by secretedpolypeptides (for instance, mitogenic factors, survival factors,cytotoxic factors, differentiation factors, neuropeptides, and hormones)which are, in turn, received and interpreted by diverse cell receptorsor membrane-bound proteins. These secreted polypeptides or signalingmolecules normally pass through the cellular secretory pathway to reachtheir site of action in the extracellular environment, usually at amembrane-bound receptor protein.

We herein describe the identification and characterization of novelpolypeptides having homology to CRTAM, designated herein as PRO258polypeptides.

13. PRO266

Protein-protein interactions include receptor and antigen complexes andsignaling mechanisms. As more is known about the structural andfunctional mechanisms underlying protein-protein interactions,protein-protein interactions can be more easily manipulated to regulatethe particular result of the protein-protein interaction. Thus, theunderlying mechanisms of protein-protein interactions are of interest tothe scientific and medical community.

All proteins containing leucine-rich repeats are thought to be involvedin protein-protein interactions. Leucine-rich repeats are short sequencemotifs present in a number of proteins with diverse functions andcellular locations. The crystal structure of ribonuclease inhibitorprotein has revealed that leucine-rich repeats correspond to beta-alphastructural units. These units are arranged so that they form a parallelbeta-sheet with one surface exposed to solvent, so that the proteinacquires an unusual, nonglobular shape. These two features have beenindicated as responsible for the protein-binding functions of proteinscontaining leucine-rich repeats. See, Kobe and Deisenhofer, TrendsBiochem. Sci., 19(10):415-421 (October 1994).

A study has been reported on leucine-rich proteoglycans which serve astissue organizers, orienting and ordering collagen fibrils duringontogeny and are involved in pathological processes such as woundhealing, tissue repair, and tumor stroma formation. Iozzo, R. V., Crit.Rev. Biochem. Mol. Biol., 32(2):141-174 (1997). Others studiesimplicating leucine rich proteins in wound healing and tissue repair areDe La Salle, C., et al., Vouv. Rev. Fr. Hematol. (Germany),37(4):215-222 (1995), reporting mutations in the leucine rich motif in acomplex associated with the bleeding disorder Bernard-Soulier syndromeand Chlemetson, K. J., Thromb. Haemost. (Germany), 74(1): 111-116 (July1995), reporting that platelets have leucine rich repeats. Anotherprotein of particular interest which has been reported to haveleucine-rich repeats is the SLIT protein which has been reported to beuseful in treating neuro-degenerative diseases such as Alzheimer'sdisease, nerve damage such as in Parkinson's disease, and for diagnosisof cancer, see, Artavanistsakonas, S. and Rothberg, J. M., WO9210518-A1by Yale University. Other studies reporting on the biological functionsof proteins having leucine-rich repeats include: Tayar, N., et al., Mol.Cell Endocrinol., (Ireland), 125(1-2):65-70 (December 1996)(gonadotropin receptor involvement); Miura, Y., et al., Nippon Rinsho(Japan), 54(7):1784-1789 (July 1996) (apoptosis involvement); Harris, P.C., et al., J. Am. Soc. Nephrol., 6(4):1125-1133 (October 1995) (kidneydisease involvement); and Ruoslahti, E. I., et al., WO9110727-A by LaJolla Cancer Research Foundation (decorin binding to transforming growthfactors involvement for treatment for cancer, wound healing andscarring).

Efforts are therefore being undertaken by both industry and academia toidentify new proteins having leucine rich repeats to better understandprotein-protein interactions, neuronal development and adhesinmolecules. Of particular interest are those proteins having leucine richrepeats and homology to known proteins having leucine rich repeats suchas the SLIT protein. We herein describe novel polypeptides havinghomology to SLIT, designated herein as PRO266 polypeptides.

14. PRO269

Thrombomodulin binds to and regulates the activity of thrombin. It isimportant in the control of blood coagulation. Thrombomodulin functionsas a natural anticoagulant by accelerating the activation of protein Cby thrombin. Soluble thrombomodulin may have therapeutic use as anantithrombotic agent with reduced risk for hemorrhage as compared withheparin. Thrombomodulin is a cell surface trans-membrane glycoprotein,present on endothelial cells and platelets. A smaller, functionallyactive form of thrombomodulin circulates in the plasma and is also foundin urine. (In Haeberli, A., Human Protein Data, VCH Oub., N.Y., 1992).Peptides having homology to thrombomodulin are particularly desirable.

We herein describe the identification and characterization of novelpolypeptides having homology to thrombomodulin, designated herein asPRO269 polypeptides.

15. PRO287

Procollagen C-proteinase enhancer protein binds to and enhances theactivity of bone morphogenic protein “BMP1”/procollagen C-proteinase(PCP). It plays a role in extracellular matrix deposition. BMP1 proteinsmay be used to induce bone and/or cartilage formation and in woundhealing and tissue repair. Therefore, procollagen C-proteinase enhancerprotein, BMP1 and proteins having homology thereto, are of interest tothe scientific and medical communities.

We herein describe the identification and characterization of novelpolypeptides having homology to procollagen C-proteinase enhancerprotein precursor and procollagen C-proteinase enhancer protein,designated herein as PRO287 polypeptides.

16. PRO214

Growth factors are molecular signals or mediators that enhances cellgrowth or proliferation, alone or in concert, by binding to specificcell surface receptors. However, there are other cellular reactions thanonly growth upon expression to growth factors. As a result, growthfactors are better characterized as multifunctional and potent cellularregulators. Their biological effects include proliferation, chemotaxisand stimulation of extracellular matrix production. Growth factors canhave both stimulatory and inhibitory effects. For example, transforminggrowth factor β (TGF-β) is highly pleiotropic and can stimulateproliferation in some cells, especially connective tissue, while being apotent inhibitor of proliferation in others, such as lymphocytes andepithelial cells.

The physiological effect of growth stimulation or inhibition by growthfactors depends upon the state of development and differentiation of thetarget tissue. The mechanism of local cellular regulation by classicalendocrine molecules involves comprehends autocrine (same cell),juxtacrine (neighbor cell), and paracrine (adjacent cells) pathways.Peptide growth factors are elements of a complex biological language,providing the basis for intercellular communication. They permit cellsto convey information between each other, mediate interaction betweencells and change gene expression. The effect of these multifunctionaland pluripotent factors is dependent on the presence or absence of otherpeptides.

Epidermal growth factor (EGF) is a conventional mitogenic factor thatstimulates the proliferation of various types of cells includingepithelial cells and fibroblasts. EGF binds to and activates the EGFreceptor (EGFR), which initiates intracellular signaling and subsequenteffects. The EGFR is expressed in neurons of the cerebral cortex,cerebellum, and hippocampus in addition to other regions of the centralnervous system (CNS). In addition, EGF is also expressed in variousregions of the CNS. Therefore, EGF acts not only on mitotic cells, butalso on postmitotic neurons. In fact, many studies have indicated thatEGF has neurotrophic or neuromodulatory effects on various types ofneurons in the CNS. For example, EGF acts directly on cultured cerebralcortical and cerebellar neurons, enhancing neurite outgrowth andsurvival. On the other hand, EGF also acts on other cell types,including septal cholinergic and mesencephalic dopaminergic neurons,indirectly through glial cells. Evidence of the effects of EGF onneurons in the CNS is accumulating, but the mechanisms of action remainessentially unknown. EGF-induced signaling in mitotic cells is betterunderstood than in postmitotic neurons. Studies of clonedpheochromocytoma PC12 cells and cultured cerebral cortical neurons havesuggested that the EGF-induced neurotrophic actions are mediated bysustained activation of the EGFR and mitogen-activated protein kinase(MAPK) in response to EGF. The sustained intracellular signalingcorrelates with the decreased rate of EGFR down-regulation, which mightdetermine the response of neuronal cells to EGF. It is likely that EGFis a multi-potent growth factor that acts upon various types of cellsincluding mitotic cells and postmitotic neurons.

EGF is produced by the salivary and Brunner's glands of thegastrointestinal system, kidney, pancreas, thyroid gland, pituitarygland, and the nervous system, and is found in body fluids such assaliva, blood, cerebrospinal fluid (CSF), urine, amniotic fluid,prostatic fluid, pancreatic juice, and breast milk, Plata-Salaman, C RPeptides 12:653-663 (1991).

EGF is mediated by its membrane specific receptor, which contains anintrinsic tyrosine kinase. Stoscheck C M et al., J. Cell Biochem. 31:135-152 (1986). EGF is believed to function by binding to theextracellular portion of its receptor which induces a transmembranesignal that activates the intrinsic tyrosine kinase.

Purification and sequence analysis of the EGF-like domain has revealedthe presence of six conserved cysteine residues which cross-bind tocreate three peptide loops, Savage C R et al., J. Biol. Chem. 248:7669-7672 (1979). It is now generally known that several other peptidescan react with the EGF receptor which share the same generalized motif.Non isolated peptides having this motif include TGF-a, amphiregulin,schwannoma-derived growth factor (SDGF), heparin-binding EGF-like growthfactors and certain virally encoded peptides (e.g., Vaccinia virus,Reisner A H, Nature 313: 801-803 (1985), Shope fibroma virus, Chang W.,et al., Mol Cell Biol. 7: 535-540 (1987), Molluscum contagiosum, PorterC D & Archard L C, J. Gen. Virol. 68:673-682 (1987), and Myxoma virus,Upton C et al., J. Virol. 61: 1271-1275 (1987). Prigent S A & Lemoine N.R., Prog. Growth Factor Res. 4: 1-24 (1992).

EGF-like domains are not confined to growth factors but have beenobserved in a variety of cell-surface and extracellular proteins whichhave interesting properties in cell adhesion, protein-proteininteraction and development, Laurence D J R & Gusterson B A, Tumor Biol.11: 229-261 (1990). These proteins include blood coagulation factors(factors VI, IX, X, XII, protein C, protein S, protein Z, tissueplasminogen activator, urokinase), extracellular matrix components(laminin, cytotactin, entactin), cell surface receptors (LDL receptor,thrombomodulin receptor) and immunity-related proteins (complement C1r,uromodulin).

Even more interesting, the general structure pattern of EGF-likeprecursors is preserved through lower organisms as well as in mammaliancells. A number of genes with developmental significance have beenidentified in invertebrates with EGF-like repeats. For example, thenotch gene of Drosophila encodes 36 tandemly arranged 40 amino acidrepeats which show homology to EGF, Wharton W et al., Cell 43:557-581(1985). Hydropathy plots indicate a putative membrane spanning domain,with the EGF-related sequences being located on the extracellular sideof the membrane. Other homeotic genes with EGF-like repeats includeDelta, 95F and 5ZD which were identified using probes based on Notch,and the nematode gene Lin-12 which encodes a putative receptor for adevelopmental signal transmitted between two specified cells.

Specifically, EGF has been shown to have potential in the preservationand maintenance of gastrointestinal mucosa and the repair of acute andchronic mucosal lesions, Konturek, P C et al., Eur. J. GastroenterolHepatol. 7 (10), 933-37 (1995), including the treatment of necrotizingenterocolitis, Zollinger-Ellison syndrome, gastrointestinal ulcerationgastrointestinal ulcerations and congenital microvillus atrophy, A.Guglietta & P B Sullivan, Eur. J. Gastroenterol Hepatol, 2(10), 945-50(1995). Additionally, EGF has been implicated in hair follicledifferentiation; C. L. du Cros, J. Invest. Dermatol. 101 (1 Suppl.),106S-113S (1993), S G Hillier, Clin. Endocrinol. 33(4), 427-28 (1990);kidney function, L. L. Hamm et al., Semin. Nephrol 13 (1): 109-15(1993), R C Harris, Am. J. Kidney Dis. 17(6): 627-30 (1991); tear fluid,G B van Setten et al., Int. Ophthalmol 15(6); 359-62 (1991); vitamin Kmediated blood coagulation, J. Stenflo et al., Blood 78(7): 1637-51(1991). EGF is also implicated various skin disease characterized byabnormal keratinocyte differentiation, e.g., psoriasis, epithelialcancers such as squamous cell carcinomas of the lung, epidermoidcarcinoma of the vulva and gliomas. King, L E et al., Am. J. Med. Sci.296: 154-158 (1988).

Of great interest is mounting evidence that genetic alterations ingrowth factors signaling pathways are closely linked to developmentalabnormalities and to chronic diseases including cancer. Aaronson S A,Science 254: 1146-1153 (1991). For example, c-erb-2 (also known asHER-2), a proto-oncogene with close structural similarity to EGFreceptor protein, is overexpressed in human breast cancer. King et al.,Science 229: 974-976 (1985); Gullick, W J, Hormones and their actions,Cooke B A et al., eds, Amsterdam, Elsevier, pp 349-360 (1986).

17. PRO317

The TGF-β supergene family, or simply TGF-β superfamily, a group ofsecreted proteins, includes a large number of related growth anddifferentiation factors expressed in virtually all phyla. Superfamilymembers bind to specific cell surface receptors that activate signaltransduction mechanisms to elicit their multifunctional cytokineeffects. Kolodziejczyk and Hall, Biochem. Cell. Biol., 74: 299-314(1996); Attisano and Wrana, Cytokine Growth Factor Rev., 7: 327-339(1996); and Hill, Cellular Signaling, 8: 533-544 (1996).

Members of this family include five distinct forms of TGF-β (Sporn andRoberts, in Peptide Growth Factors and Their Receptors, Sporn andRoberts, eds. (Springer-Verlag: Berlin, 1990) pp. 419-472), as well asthe differentiation factors vg1 (Weeks and Melton, Cell, 51: 861-867(1987)) and DPP-C polypeptide (Padgett et al., Nature, 325: 81-84(1987)), the hormones activin and inhibin (Mason et al, Nature, 318:659-663 (1985); Mason et al., Growth Factors, 1: 77-88 (1987)), theMullerian-inhibiting substance (MIS) (Cate et al., Cell 45: 685-698(1986)), the bone morphogenetic proteins (BMPs) (Wozney et al., Science,242: 1528-1534 (1988); PCT WO 88/00205 published Jan. 14, 1988; U.S.Pat. No. 4,877,864 issued Oct. 31, 1989), the developmentally regulatedproteins Vgr-1 (Lyons et al., Proc. Natl. Acad. Sci. USA. 86: 4554-4558(1989)) and Vgr-2 (Jones et al., Molec. Endocrinol., 6: 1961-1968(1992)), the mouse growth differentiation factor (GDF), such as GDF-3and GDF-9 (Kingsley, Genes Dev., 8: 133-146 (1994); McPherron and Lee,J. Biol. Chem., 268: 3444-3449 (1993)), the mouse lefty/Stra1 (Meno etal., Nature, 381: 151-155 (1996); Bouillet et al., Dev. Biol., 170:420-433 (1995)), glial cell line-derived neurotrophic factor (GDNF) (Linet al., Science, 260: 1130-1132 neurturin (Kotzbauer et al., Nature,384: 467-470 (1996)), and endometrial bleeding-associated factor (EBAF)(Kothapalli et al., J. Clin. Invest., 99: 2342-2350 (1997)). The subsetBMP-2A and BMP-2B is approximately 75% homologous in sequence to DPP-Cand may represent the mammalian equivalent of that protein.

The proteins of the TGF-β superfamily are disulfide-linked homo- orheterodimners encoded by larger precursor polypeptide chains containinga hydrophobic signal sequence, a long and relatively poorly conservedN-terminal pro region of several hundred amino acids, a cleavage site(usually polybasic), and a shorter and more highly conserved C-terminalregion. This C-terminal region corresponds to the processed matureprotein and contains approximately 100 amino acids with a characteristiccysteine motif, i.e., the conservation of seven of the nine cysteineresidues of TGF-β among all known family members. Although the positionof the cleavage site between the mature and pro regions varies among thefamily members, the C-terminus of all of the proteins is in theidentical position, ending in the sequence Cys-X-Cys-X, but differing inevery case from the TGF-β consensus C-terminus of Cys-Lys-Cys-Ser. Spornand Roberts, 1990, supra.

There are at least five forms of TGF-β currently identified, TGF-β1,TGF-β2, TGF-β3, TGF-β4, and TGF-β5. The activated form of TGF-β1 is ahomodimer formed by dimerization of the carboxy-terminal 112 amino acidsof a 390 amino acid precursor. Recombinant TGF-β1 has been cloned(Derynck et al., Nature, 316:701-705 (1985)) and expressed in Chinesehamster ovary cells (Gentry et al., Mol. Cell. Biol. 7:3418-3427(1987)). Additionally, recombinant human TGF-β2 (deMartin et al., EMBOJ., 6: 3673 (1987)), as well as human and porcine TGF-β3 (Derynck etal., EMBO J., 7: 3737-3743 (1988); ten Dijke et al., Proc. Natl. Acad.Sci. USA, 85: 4715 (1988)) have been cloned. TGF-β2 has a precursor formof 414 amino acids and is also processed to a homodimer from thecarboxy-terminal 112 amino acids that shares approximately 70% homologywith the active form of TGF-β1 (Marquardt et al., J. Biol. Chem., 262:12127 (1987)). See also EP 200,341; 169,016; 268,561; and 267,463; U.S.Pat. No. 4,774,322; Cheifetz et al., Cell, 48: 409-415 (1987); Jakowlewet al., Molecular Endocrin., 2: 747-755 (1988); Derynck et al., J. Biol.Chem., 261: 4377-4379 (1986); Sharples et al., DNA, 6: 239-244 (1987);Derynck et al., Nucl. Acids. Res., 15: 3188-3189 (1987); Derynck et al.,Nucl. Acids. Res., 15: 3187 (1987); Seyedin et al., J. Biol. Chem., 261:5693-5695 (1986); Madisen al., DNA, 7: 1-8 (1988); and Hanks et al.,Proc. Natl. Acad. Sci. (U.S.A.), 85: 79-82 (1988).

TGF-β4 and TGF-β5 were cloned from a chicken chondrocyte cDNA library(Jakowlew et al., Molec. Endocrinol., 2: 1186-1195 (1988)) and from afrog oocyte cDNA library, respectively.

The pro region of TGF-β associates non-covalently with the mature TGF-βdimer (Wakefield et al., J. Biol. Chem., 263: 7646-7654 (1988);Wakefield et al., Growth Factors, 1: 203-218 (1989)), and the proregions are found to be necessary for proper folding and secretion ofthe active mature dimers of both TGF-β and activin (Gray and Mason,Science, 247: 1328-1330 (1990)). The association between the mature andpro regions of TGF-β masks the biological activity of the mature dimer,resulting in formation of an inactive latent form. Latency is not aconstant of the TGF-β superfamily, since the presence of the pro regionhas no effect on activin or inhibin biological activity.

A unifying feature of the biology of the proteins from the TGF-βsuperfamily is their ability to regulate developmental processes. TGF-βhas been shown to have numerous regulatory actions on a wide variety ofboth normal and neoplastic cells. TGF-β is multifunctional, as it caneither stimulate or inhibit cell proliferation, differentiation, andother critical processes in cell function (Sporn and Roberts, supra).

One member of the TGF-β superfamily, EBAF, is expressed in endometriumonly in the late secretory phase and during abnormal endometrialbleeding. Kothapalli et al., J. Clin. Invest., 99: 2342-2350 (1997).Human endometrium is unique in that it is the only tissue in the bodythat bleeds at regular intervals. In addition, abnormal endometrialbleeding is one of the most common manifestations of gynecologicaldiseases, and is a prime indication for hysterectomy. In situhybridization showed that the mRNA of EBAF was expressed in the stromawithout any significant mRNA expression in the endometrial glands orendothelial cells.

The predicted protein sequence of EBAF showed a strong homology to theprotein encoded by mouse lefty/stra3 of the TGF-β superfamily. A motifsearch revealed that the predicted EBAF protein contains most of thecysteine residues which are conserved among the TGF-β-related proteinsand which are necessary for the formation of the cysteine knotstructure. The EBAF sequence contains an additional cysteine residue, 12amino acids upstream from the first conserved cysteine residue. The onlyother family members known to contain an additional cysteine residue areTGF-βs, inhibins, and GDF-3. EBAF, similar to LEFTY, GDF-3/Vgr2, andGDF-9, lacks the cysteine residue that is known to form theintermolecular disulfide bond. Therefore, EBAF appears to be anadditional member of the TGF-β superfamily with an unpaired cysteineresidue that may not exist as a dimer. However, hydrophobic contactsbetween the two monomer subunits may promote dimer formation.Fluorescence in situ hybridization showed that the ebaf gene is locatedon human chromosome 1 at band q42.1.

Additional members of the TGF-β superfamily, such as those related toEBAF, are being searched for by industry and academics. We hereindescribe the identification and characterization of novel polypeptideshaving homology to EBAF, designated herein as PRO317 polypeptides.

18. PRO301

The widespread occurrence of cancer has prompted the devotion ofconsiderable resources and discovering new treatments of treatment. Oneparticular method involves the creation of tumor or cancer specificmonoclonal antibodies (mAbs) which are specific to tumor antigens. SuchmAbs, which can distinguish between normal and cancerous cells areuseful in the diagnosis, prognosis and treatment of the disease.Particular antigens are known to be associated with neoplastic diseases,such as colorectal cancer.

One particular antigen, the A33 antigen is expressed in more than 90% ofprimary or metastatic colon cancers as well as normal colon epithelium.Since colon cancer is a widespread disease, early diagnosis andtreatment is an important medical goal. Diagnosis and treatment of coloncancer can be implemented using monoclonal antibodies (mAbs) specifictherefore having fluorescent, nuclear magnetic or radioactive tags.Radioactive gene, toxins and/or drug tagged mAbs can be used fortreatment in situ with minimal patient description. mAbs can also beused to diagnose during the diagnosis and treatment of colon cancers.For example, when the serum levels of the A33 antigen are elevated in apatient, a drop of the levels after surgery would indicate the tumorresection was successful. On the other hand, a subsequent rise in serumA33 antigen levels after surgery would indicate that metastases of theoriginal tumor may have formed or that new primary tumors may haveappeared. Such monoclonal antibodies can be used in lieu of, or inconjunction with surgery and/or other chemotherapies. For example, U.S.Pat. No. 4,579,827 and U.S. Ser. No. 424,991 (E.P. 199,141) are directedto therapeutic administration of monoclonal antibodies, the latter ofwhich relates to the application of anti-A33 mAb.

Many cancers of epithelial origin have adenovirus receptors. In fact,adenovirus-derived vectors have been proposed as a means of insertingantisense nucleic acids into tumors (U.S. Pat. No. 5,518,885). Thus, theassociation of viral receptors with neoplastic tumors is not unexpected.

We herein describe the identification and characterization of novelpolypeptides having homology to certain cancer-associated antigens,designated herein as PRO301 polypeptides.

19. PRO224

Cholesterol uptake can have serious implications on one's health.Cholesterol uptake provides cells with most of the cholesterol theyrequire for membrane synthesis. If this uptake is blocked, cholesterolaccumulates in the blood and can contribute to the formation ofatherosclerotic plaques in blood vessel walls. Most cholesterol istransported in the blood bound to protein in the form of complexes knownas low-density lipoproteins (LDLs). LDLs are endocytosed into cells viaLDL receptor proteins. Therefore, LDL receptor proteins, and proteinshaving homology thereto, are of interest to the scientific and medicalcommunities.

Membrane-bound proteins and receptors can play an important role in theformation, differentiation and maintenance of multicellular organisms.The LDL receptors are an example of membrane-bound proteins which areinvolved in the synthesis and formation of cell membranes, wherein thehealth of an individual is affected directly and indirectly by itsfunction. Many membrane-bound proteins act as receptors such as the LDLreceptor. These receptors can function to endocytose substrates or theycan function as a receptor for a channel. Other membrane-bound proteinsfunction as signals or antigens.

Membrane-bound proteins and receptor molecules have various industrialapplications, including as pharmaceutical and diagnostic agents. Themembrane-bound proteins can also be employed for screening of potentialpeptide or small molecule regulators of the relevant receptor/ligandinteraction. In the case of the LDL receptor, it is desirable to findmolecules which enhance endocytosis so as to lower blood cholesterollevels and plaque formation. It is also desirable to identify moleculeswhich inhibit endocytosis so that these molecules can be avoided orregulated by individuals having high blood cholesterol. Polypeptideswhich are homologous to lipoprotein receptors but which do not functionas lipoprotein receptors are also of interest in the determination ofthe function of the fragments which show homology.

The following studies report on previously known low density lipoproteinreceptors and related proteins including apolipoproteins: Sawamura, etal., Nippon Chemiphar Co, Japan patent application J09098787; Novak, S.,et al., J. Biol. Chem., 271:(20)11732-6 (1996); Blaas, D., J. Virol.,69(11)7244-7 (November 1995); Scott J., J. Inherit. Metab. Dis. (UK),9/Supp. 1 (3-16) (1986); Yamamoto, et al., Cell, 39:27-38 (1984);Rebece, et al., Neurobiol. Aging, 15:5117 (1994); Novak, S., et al., J.Biol. Chemistry, 271:11732-11736(1996); and Sestavel and Fruchart, CellMol. Biol., 40(4):461-81 (June 1994). These publications and otherspublished prior to the filing of this application provide furtherbackground to peptides already known in the art.

Efforts are being undertaken by both industry and academia to identifynew, native membrane-bound receptor proteins, particularly those havinghomology to lipoprotein receptors. We herein describe the identificationand characterization of novel polypeptides having homology tolipoprotein receptors, designated herein as PRO224 polypeptides.

20. PRO222

Complement is a group of proteins found in the blood that are importantin humoral immunity and inflammation. Complement proteins aresequentially activated by antigen-antibody complexes or by proteolyticenzymes. When activated, complement proteins kill bacteria and othermicroorganisms, affect vascular permeability, release histamine andattract white blood cells. Complement also enhances phagocytosis whenbound to target cells. In order to prevent harm to autologous cells, thecomplement activation pathway is tightly regulated.

Deficiencies in the regulation of complement activation or in thecomplement proteins themselves may lead to immune-complex diseases, suchas systemic lupus erythematosus, and may result in increasedsusceptibility to bacterial infection. In all cases, early detection ofcomplement deficiency is desirable so that the patient can begintreatment. Thus, research efforts are currently directed towardidentification of soluble and membrane proteins that regulate complementactivation.

Proteins known to be important in regulating complement activation inhumans include Factor H and Complement receptor type 1 (CR1). Factor His a 150 kD soluble serum protein that interacts with complement proteinC3b to accelerate the decay of C3 convertase and acts as a cofactor forFactor I-mediated cleavage of complement protein C4b. Complementreceptor type 1 is a 190-280 kD membrane bound protein found in mastcells and most blood cells. CR1 interacts with complement proteins C3b,C4b, and iC3b to accelerate dissociation of C3 convertases, acts as acofactor for Factor I-mediated cleavage of C3b and C4b, and binds immunecomplexes and promotes their dissolution and phagocytosis.

Proteins which have homology to complement proteins are of particularinterest to the medical and industrial communities. Often, proteinshaving homology to each other have similar function. It is also ofinterest when proteins having homology do not have similar functions,indicating that certain structural motifs identify information otherthan function, such as locality of function.

Efforts are being undertaken by both industry and academia to identifynew, native secreted and membrane-bound proteins, particularly thosehaving homology to known proteins involved in the complement pathway.Proteins involved in the complement pathway were reviewed in BirminghamD J (1995), Critical Reviews in Immunology, 15(2):133-154 and in Abbas AK, et al. (1994) Cellular and Molecular Immunology, 2nd Ed. W.B.Saunders Company, Philadelphia, pp 295-315.

We herein describe the identification and characterization of novelpolypeptides having homology to complement receptors, designated hereinas PRO222 polypeptides.

21. PRO234

The successful function of many systems within multicellular organismsis dependent on cell-cell interactions. Such interactions are affectedby the alignment of particular ligands with particular receptors in amanner which allows for ligand-receptor binding and thus a cell-celladhesion. While protein-protein interactions in cell recognition havebeen recognized for some time, only recently has the role ofcarbohydrates in physiologically relevant recognition been widelyconsidered (see B. K. Brandley et al., J. Leuk. Biol. 40: 97 (1986) andN. Sharon et al., Science 246: 227 (1989). Oligosaccharides are wellpositioned to act as recognition novel lectins due to their cell surfacelocation and structural diversity. Many oligosaccharide structures canbe created through the differential activities of a smaller number ofglycosyltransferases. The diverse structures of oligosaccharides can begenerated by transcription of relatively few gene products, whichsuggests that the oligosaccharides are a plausible mechanism by which isdirected a wide range of cell-cell interactions. Examples ofdifferential expression of cell surface carbohydrates and putativecarbohydrate binding proteins (lectins) on interacting cells have beendescribed (J. Dodd & T. M. Jessel, J. Neurosci. 5: 3278 (1985); L. J.Regan et al., Proc. Natl. Acad. Sci. USA 83: 2248 (1986); M.Constantine-Paton et al., Nature 324: 459 (1986); and M. Tiemeyer etal., J. Biol. Chem. 263: 1671 (1989). One interesting member of thelectin family are selecting.

The migration of leukocytes to sites of acute or chronic inflammationinvolves adhesive interactions between these cells and the endothelium.This specific adhesion is the initial event in the cascade that isinitiated by inflammatory insults, and it is, therefore, of paramountimportance to the regulated defense of the organism.

The types of cell adhesion molecules that are involved in theinteraction between leukocytes and the endothelium during aninflammatory response currently stands at four: (1) selecting; (2)(carbohydrate and glycoprotein) ligands for selecting; (3) integrins;and (4) integrin ligands, which are members of the immunoglobulin genesuperfamily.

The selecting are cell adhesion molecules that are unified bothstructurally and functionally. Structurally, selectins are characterizedby the inclusion of a domain with homology to a calcium-dependent lectin(C-lectins), an epidermal growth factor (egf)-like domain and severalcomplement binding-like domains, Bevilacqua, M. P. et al., Science 243:1160-1165 (1989); Johnston et al., Cell 56: 1033-1044 (1989); Lasky etal, Cell 56: 1045-1055 (1989); Siegalman, M. et al., Science 243:1165-1172 (1989); Stoolman, L. M., Cell 56: 907-910 (1989).Functionally, selectins share the common property of their ability tomediate cell binding through interactions between their lectin domainsand cell surface carbohydrate ligands (Brandley, B, et al., Cell 63,861-863 (1990); Springer, T. and Lasky, L. A., Nature 349, 19-197(1991); Bevilacqua, M. P. and Nelson, R. M., J. Clin. Invest. 91 379-387(1993) and Tedder et al., J. Exp. Med. 170: 123-133 (1989).

There are three members identified so far in the selectin family of celladhesion molecules: L-selectin (also called peripheral lymph node homingreceptor (pnHR), LEC-CAM-1, LAM-1, gp90^(MEL), gp100^(MEL), gp110^(MEL),MEL-14 antigen, Leu-8 antigen, TQ-1 antigen, DREG antigen), E-selectin(LEC-CAM-2, LECAM-2, ELAM-1) and P-selectin (LEC-CAM-3, LECAM-3,GMP-140, PADGEM).

The identification of the C-lectin domain has led to an intense effortto define carbohydrate binding ligands for proteins containing suchdomains. E-selectin is believed to recognize the carbohydrate sequenceNeuNAcα2-3Galβ1-4(Fucα1-3)GlcNAc (sialyl-Lewis x, or sLe^(x)) andrelated oligosaccharides, Berg et al., J. Biol. Chem. 265:14869-14872(1991); Lowe et al, Cell 63: 475-484(1990); Phillips et al.,Science 250: 1130-1132 (1990); Tiemeyer et al., Proc. Natl. Acad. Sci.USA 88: 1138-1142 (1991).

L-selectin, which comprises a lectin domain, performs its adhesivefunction by recognizing carbohydrate-containing ligands on endothelialcells. L-selectin is expressed on the surface of leukocytes, such aslymphocytes, neutrophils, monocytes and eosinophils, and is involvedwith the trafficking of lymphocytes to peripheral lymphoid tissues(Gallatin et al., Nature 303: 30-34 (1983)) and with acuteneutrophil-medicated inflammatory responses (Watson, S. R., Nature 349:164-167 (1991)). The amino acid sequence of L-selectin and the encodingnucleic acid sequence are, for example, disclosed in U.S. Pat. No.5,098,833 issued Mar. 24, 1992.

L-selectin (LECAM-1) is particularly interesting because of its abilityto block neutrophil influx (Watson et al., Nature 349: 164-167 (1991).It is expressed in chronic lymphocytic leukemia cells which bind to HEV(Spertini et al., Nature 349: 691-694 (1991). It is also believed thatHEV structures at sites of chronic inflammation are associated with thesymptoms of diseases such as rheumatoid arthritis, psoriasis andmultiple sclerosis.

E-selectin (ELAM-1), is particularly interesting because of itstransient expression on endothelial cells in response to IL-1 or TNF.Bevilacqua et al., Science 243: 1160 (1989). The time course of thisinduced expression (2-8 h) suggests a role for this receptor in initialneutrophil induced extravasation in response to infection and injury. Ithas further been reported that anti-ELAM-1 antibody blocks the influx ofneutrophils in a primate asthma model and thus is beneficial forpreventing airway obstruction resulting from the inflammatory response.Gundel et al., J. Clin. Invest. 88: 1407 (1991).

The adhesion of circulating neutrophils to stimulated vascularendothelium is a primary event of the inflammatory response. P-selectinhas been reported to recognize the Lewis x structure (Galβ1-4(Fucα1-3)GlcNAc), Larsen et al., Cell 63: 467-474(1990). Others report that anadditional terminal linked sialic acid is required for high affinitybinding, Moore et al., J. Cell Biol. 112: 491-499 (1991). P-selectin hasbeen shown to be significant in acute lung injury. Anti-P-selectinantibody has been shown to have strong protective effects in a rodentlung injury model. M. S. Mulligan et al., J. Clin. Invest. 90: 1600(1991).

We herein describe the identification and characterization of novelpolypeptides having homology to lectin proteins, herein designated asPRO234 polypeptides.

22. PRO231

Some of the most important proteins involved in the above describedregulation and modulation of cellular processes are the enzymes whichregulate levels of protein phosphorylation in the cell. For example, itis known that the transduction of signals that regulate cell growth anddifferentiation is regulated at least in part by phosphorylation anddephosphorylation of various cellular proteins. The enzymes thatcatalyze these processes include the protein kinases, which function tophosphorylate various cellular proteins, and the protein phosphatases,which function to remove phosphate residues from various cellularproteins. The balance of the level of protein phosphorylation in thecell is thus mediated by the relative activities of these two types ofenzymes.

Protein phosphatases represent a growing family of enzymes that arefound in many diverse forms, including both membrane-bound and solubleforms. While many protein phosphatases have been described, thefunctions of only a very few are beginning to be understood (Tonks,Semin. Cell Biol. 4:373-453 (1993) and Dixon, Recent Prog. Horm. Res.51:405-414 (1996)). However, in general, it appears that many of theprotein phosphatases function to modulate the positive or negativesignals induced by various protein kinases. Therefore, it is likely thatprotein phosphatases play critical roles in numerous and diversecellular processes.

Given the physiological importance of the protein phosphatases, effortsare being undertaken by both industry and academia to identify new,native phosphatase proteins. Many of these efforts are focused on thescreening of mammalian recombinant DNA libraries to identify the codingsequences for novel phosphatase proteins. Examples of screening methodsand techniques are described in the literature [see, for example, Kleinet al., Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No.5,536,637)].

We herein describe the identification and characterization of novelpolypeptides having homology to acid phosphatases, designated herein asPRO231 polypeptides.

23. PRO229

Scavenger receptors are known to protect IgG molecules from catabolicdegradation. Riechmann and Hollinger, Nature Biotechnology, 15:617(1997). In particular, studies of the CH2 and CH3 domains have shownthat specific sequences of these domains are important in determiningthe half-lives of antibodies. Ellerson, et al., J. Immunol., 116: 510(1976); Yasmeen, et al., J. Immunol. 116: 518 (1976; Pollock, et al.,Eur. J. Immunol., 20: 2021 (1990). Scavenger receptor proteins andantibodies thereto are further reported in U.S. Pat. No. 5,510,466 toKrieger, et al. Due to the ability of scavenger receptors to increasethe half-life of polypeptides and their involvement in immune function,molecules having homology to scavenger receptors are of importance tothe scientific and medical community.

Efforts are being undertaken by both industry and academia to identifynew, native secreted and membrane-bound receptor proteins, particularlythose having homology to scavenger receptors. Many efforts are focusedon the screening of mammalian recombinant DNA libraries to identify thecoding sequences for novel secreted and membrane-bound receptorproteins. Examples of screening methods and techniques are described inthe literature [see, for example, Klein et al., Proc. Natl. Acad. Sci.93:7108-7113 (1996); U.S. Pat. No. 5,536,637)].

We herein describe the identification and characterization of novelpolypeptides having homology to scavenger receptors, designated hereinas PRO229 polypeptides.

24. PRO238

Oxygen free radicals and antioxidants appear to play an important rolein the central nervous system after cerebral ischemia and reperfusion.Moreover, cardiac injury, related to ischaemia and reperfusion has beenreported to be caused by the action of free radicals. Additionally,studies have reported that the redox state of the cell is a pivotaldeterminant of the fate of the cells. Furthermore, reactive oxygenspecies have been reported to be cytotoxic, causing inflammatorydisease, including tissue necrosis, organ failure, atherosclerosis,infertility, birth defects, premature aging, mutations and malignancy.Thus, the control of oxidation and reduction is important for a numberof reasons including for control and prevention of strokes, heartattacks, oxidative stress and hypertension. In this regard, reductases,and particularly, oxidoreductases, are of interest. Publications furtherdescribing this subject matter include Kelsey, et al., Br. J. Cancer,76(7):852-4 (1997); Friedrich and Weiss, J. Theor. Biol., 187(4):529-40(1997) and Pieulle, et al., J. Bacteriol., 179(18):5684-92 (1997).

Efforts are being undertaken by both industry and academia to identifynew, native secreted and membrane-bound receptor proteins, particularlysecreted proteins which have homology to reductase. Many efforts arefocused on the screening of mammalian recombinant DNA libraries toidentify the coding sequences for novel secreted and membrane-boundreceptor proteins. Examples of screening methods and techniques aredescribed in the literature [see, for example, Klein et al., Proc. Natl.Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No. 5,536,637)].

We herein describe the identification and characterization of novelpolypeptides having homology to reductase, designated herein as PRO238polypeptides.

25. PRO233

Studies have reported that the redox state of the cell is an importantdeterminant of the fate of the cell. Furthermore, reactive oxygenspecies have been reported to be cytotoxic, causing inflammatorydisease, including tissue necrosis, organ failure, atherosclerosis,infertility, birth defects, premature aging, mutations and malignancy.Thus, the control of oxidation and reduction is important for a numberof reasons, including the control and prevention of strokes, heartattacks, oxidative stress and hypertension. Oxygen free radicals andantioxidants appear to play an important role in the central nervoussystem after cerebral ischemia and reperfusion. Moreover, cardiacinjury, related to ischaemia and reperfusion has been reported to becaused by the action of free radicals. In this regard, reductases, andparticularly, oxidoreductases, are of interest. In addition, thetranscription factors, NF-kappa B and AP-1, are known to be regulated byredox state and to affect the expression of a large variety of genesthought to be involved in the pathogenesis of AIDS, cancer,atherosclerosis and diabetic complications. Publications furtherdescribing this subject matter include Kelsey, et al., Br. J. Cancer,76(7):852-4 (1997); Friedrich and Weiss, J. Theor. Biol., 187(4):529-40(1997) and Pieulle, et al., J. Bacteriol., 179(18):5684-92 (1997). Giventhe physiological importance of redox reactions in vivo, efforts arecurrently being under taken to identify new, native proteins which areinvolved in redox reactions. We describe herein the identification ofnovel polypeptides which have homology to reductase, designated hereinas PRO233 polypeptides.

26. PRO223

The carboxypeptidase family of exopeptidases constitutes a diverse groupof enzymes that hydrolyze carboxyl-terminal amide bonds in polypeptides,wherein a large number of mammalian tissues produce these enzymes. Manyof the carboxypeptidase enzymes that have been identified to dateexhibit rather strong cleavage specificities for certain amino acids inpolypeptides. For example, carboxypeptidase enzymes have been identifiedwhich prefer lysine, arginine, serine or amino acids with eitheraromatic or branched aliphatic side chains as substrates at the carboxylterminus of the polypeptide.

With regard to the serine carboxypeptidases, such amino acid specificenzymes have been identified from a variety of different mammalian andnon-mammalian organisms. The mammalian serine carboxypeptidase enzymesplay important roles in many different biological processes including,for example, protein digestion, activation, inactivation, or modulationof peptide hormone activity, and alteration of the physical propertiesof proteins and enzymes.

In light of the physiological importance of the serinecarboxypeptidases, efforts are being undertaken by both industry andacademia to identify new, native secreted and membrane-bound receptorproteins and specifically novel carboxypeptidases. Many of these effortsare focused on the screening of mammalian recombinant DNA libraries toidentify the coding sequences for novel secreted and membrane-boundreceptor proteins. We describe herein novel polypeptides having homologyto one or more serine carboxypeptidase polypeptides, designated hereinas PRO223 polypeptides.

27. PRO235

Plexin was first identified in Xenopus tadpole nervous system as amembrane glycoprotein which was shown to mediate cell adhesion via ahomophilic binding mechanism in the presence of calcium ions. Strongevolutionary conservation between Xenopus, mouse and human homologs ofplexin has been observed. [Kaneyama et al., Biochem. And Biophys. Res.Comm. 226:524-529 (1996)]. Given the physiological importance of celladhesion mechanisms in vivo, efforts are currently being under taken toidentify new, native proteins which are involved in cell adhesion. Wedescribe herein the identification of a novel polypeptide which hashomology to plexin, designated herein as PRO235.

28. PRO236 and PRO262

β-galactosidase is a well known enzymatic protein which functions tohydrolyze β-galactoside molecules. β-galactosidase has been employed fora variety of different applications, both in vitro and in vivo and hasproven to be an extremely useful research tool. As such, there is aninterest in obtaining novel polypeptides which exhibit homology to theβ-galactosidase polypeptide.

Given the strong interest in obtaining novel polypeptides havinghomology to β-galactosidase, efforts are currently being undertaken byboth industry and academia to identify new, native β-galactosidasehomolog proteins. Many of these efforts are focused on the screening ofmammalian recombinant DNA libraries to identify the coding sequences fornovel β-galactosidase-like proteins. Examples of screening methods andtechniques are described in the literature [see, for example, Klein etal., Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No.5,536,637)]. We herein describe novel poylpeptides having siginificanthomology to the β-galactosidase enzyme, designated herein as PRO236 andPRO262 polypeptides.

29. PRO239

Densin is a glycoprotein which has been isolated from the brain whichhas all the hallmarks of an adhesion molecule. It is highly concentratedat synaptic sites in the brain and is expressed prominently in dendriticprocesses in developing neurons. Densin has been characterized as amember of the O-linked sialoglycoproteins. Densin has relevance tomedically important processes such as regeneration. Given thephysiological importance of synaptic processes and cell adhesionmechanisms in vivo, efforts are currently being under taken to identifynew, native proteins which are involved in synaptic machinery and celladhesion. We describe herein the identification of novel polypeptideswhich have homology to densin, designated herein as PRO239 polypeptides.

30. PRO257

Ebnerin is a cell surface protein associated with von Ebner glands inmammals. Efforts are being undertaken by both industry and academia toidentify new, native cell surface receptor proteins and specificallythose which possess sequence homology to cell surface proteins such asebnerin. Many of these efforts are focused on the screening of mammalianrecombinant DNA libraries to identify the coding sequences for novelreceptor proteins. We herein describe the identification of novelpolypeptides having significant homology to the von Ebner'sgland-associated protein ebnerin, designated herein as PRO257polypeptides.

31. PRO260

Fucosidases are enzymes that remove fucose residues from fucosecontaining proteoglycans. In some pathological conditions, such ascancer, rheumatoid arthritis, and diabetes, there is an abnormalfucosylation of serum proteins. Therefore, fucosidases, and proteinshaving homology to fucosidase, are of importance to the study andabrogation of these conditions. In particular, proteins having homologyto the alpha-1-fucosidase precursor are of interest. Fucosidases andfucosidase inhibitors are further described in U.S. Pat. Nos. 5,637,490,5,382,709, 5,240,707, 5,153,325, 5,100,797, 5,096,909 and 5,017,704.Studies are also reported in Valk, et al., J. Virol., 71(9):6796 (1997),Aktogu, et al., Monaldi. Arch. Chest Dis. (Italy), 52(2):118(1997) andFocarelli, et al., Biochem. Biophys. Res. Commun. (U.S.), 234(1):54(1997).

Efforts are being undertaken by both industry and academia to identifynew, native secreted and membrane-bound receptor proteins. Of particularinterest are proteins having homology to the alpha-1-fucosidaseprecursor. Many efforts are focused on the screening of mammalianrecombinant DNA libraries to identify the coding sequences for novelsecreted and membrane-bound receptor proteins. Examples of screeningmethods and techniques are described in the literature [see, forexample, Klein et al., Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S.Pat. No. 5,536,637)].

We herein describe the identification and characterization of novelpolypeptides having homology to fucosidases, designated herein as PRO260polypeptides.

32. PRO263

CD44 is a cell surface adhesion molecule involved in cell-cell andcell-matrix interactions. Hyaluronic acid, a component of theextracellular matrix is a major ligand. Other ligands include collagen,fibronectin, laminin, chrondroitin sulfate, mucosal addressin, serglycinand osteoponin. CD44 is also important in regulating cell traffic, lymphnode homing, transmission of growth signals, and presentation ofchemokines and growth factors to traveling cells. CD44 surface proteinsare associated with metastatic tumors and CD44 has been used as a markerfor HIV infection. Certain splice variants are associated withmetastasis and poor prognosis of cancer patients. Therefore, moleculeshaving homology with CD44 are of particular interest, as their homologyindicates that they may have functions related to those functions ofCD44. CD44 is further described in U.S. Pat. Nos. 5,506,119, 5,504,194and 5,108,904; Gerberick, et al., Toxicol. Appl. Pharmacol., 146(1):1(1997); Wittig, et al., Immunol. Letters (Netherlands), 57(1-3):217(1997); and Oliveira and Odell, Oral Oncol. (England), 33(4):260 (1997).

Efforts are being undertaken by both industry and academia to identifynew, native secreted and membrane-bound receptor proteins, particularlytransmembrane proteins with homology to CD44 antigen. Many efforts arefocused on the screening of mammalian recombinant DNA libraries toidentify the coding sequences for novel secreted and membrane-boundreceptor proteins. Examples of screening methods and techniques aredescribed in the literature [see, for example, Klein et al., Proc. Natl.Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No. 5,536,637)].

We herein describe the identification and characterization of novelpolypeptides having homology to CD44 antigen, designated herein asPRO263 polypeptides.

33. PRO270

Thioredoxins effect reduction-oxidation (redox) state. Many diseases arepotentially related to redox state and reactive oxygen species may playa role in many important biological processes. The transcriptionfactors, NF-kappa B and AP-1, are regulated by redox state and are knownto affect the expression of a large variety of genes thought to beinvolved in the pathogenesis of AIDS, cancer, atherosclerosis anddiabetic complications. Such proteins may also play a role in cellularantioxidant defense, and in pathological conditions involving oxidativestress such as stroke and inflammation in addition to having a role inapoptosis. Therefore, thioredoxins, and proteins having homologythereto, are of interest to the scientific and medical communities.

We herein describe the identification and characterization of novelpolypeptides having homology to thioredoxin, designated herein as PRO270polypeptides.

34. PRO271

The proteoglycan link protein is a protein which is intimatelyassociated with various extracellular matrix proteins and morespecifically with proteins such as collagen. For example, one primarycomponent of collagen is a large proteoglycan called aggrecan. Thismolecule is retained by binding to the glycosaminoglycan hyaluronanthrough the amino terminal G1 globular domain of the core protein. Thisbinding is stabilized by the proteoglycan link protein which is aprotein that is also associated with other tissues containing hyaluronanbinding proteoglycans such as versican.

Link protein has been identified as a potential target for autoimmuneantibodies in individuals who suffer from juvenile rheumatoid arthritis(see Guerassimov et al., J. Rheumatology 24(5):959-964 (1997)). As such,there is strong interest in identifying novel proteins having homologyto link protein. We herein describe the identification andcharacterization of novel polypeptides having such homology, designatedherein as PRO271 polypeptides.

35. PRO272

Reticulocalbin is an endoplasmic reticular protein which may be involvedin protein transport and luminal protein processing. Reticulocalbinresides in the lumen of the endopladsmic rerticulum, is known to bindcalcium, and may be involved in a luminal retention mechanism of theendoplasmic reticulum. It contains six domains of the EF-hand motifassociated with high affinity calcium binding. We describe herein theidentification and characterization of a novel polypeptide which hashomology to the reticulocalbin protein, designated herein as PRO272.

36. PRO294

Collagen, a naturally occurring protein, finds wide application inindustry. Chemically hydrolyzed natural collagen can be denatured andrenatured by heating and cooling to produce gelatin, which is used inphotographic and medical, among other applications. Collagen hasimportant properties such as the ability to form interchain aggregateshaving a conformation designated as a triple helix. We herein describethe identification and characterization of a novel polypeptide which hashomology to portions of the collagen molecule, designated herein asPRO294.

37. PRO295

The integrins comprise a supergene family of cell-surface glycoproteinreceptors that promote cellular adhesion. Each cell has numerousreceptors that define its cell adhesive capabilities. Integrins areinvolved in a wide variety of interaction between cells and other cellsor matrix components. The integrins are of particular importance inregulating movement and function of immune system cells The plateletIIb/IIIA integrin complex is of particular importance in regulatingplatelet aggregation. A member of the integrin family, integrin β-6, isexpressed on epithelial cells and modulates epithelial inflammation.Another integrin, leucocyte-associated antigen-1 (LFA-1) is important inthe adhesion of lymphocytes during an immune response. The integrins areexpressed as heterodimers of non-covalently associated alpha and betasubunits. Given the physiological importance of cell adhesion mechanismsin vivo, efforts are currently being under taken to identify new, nativeproteins which are involved in cell adhesion. We describe herein theidentification and characterization of a novel polypeptide which hashomology to integrin, designated herein as PRO295.

38. PRO293

Protein-protein interactions include receptor and antigen complexes andsignaling mechanisms. As more is known about the structural andfunctional mechanisms underlying protein-protein interactions,protein-protein interactions can be more easily manipulated to regulatethe particular result of the protein-protein interaction. Thus, theunderlying mechanisms of protein-protein interactions are of interest tothe scientific and medical community.

All proteins containing leucine-rich repeats are thought to be involvedin protein-protein interactions. Leucine-rich repeats are short sequencemotifs present in a number of proteins with diverse functions andcellular locations. The crystal structure of ribonuclease inhibitorprotein has revealed that leucine-rich repeats correspond to beta-alphastructural units. These units are arranged so that they form a parallelbeta-sheet with one surface exposed to solvent, so that the proteinacquires an unusual, nonglubular shape. These two features have beenindicated as responsible for the protein-binding functions of proteinscontaining leucine-rich repeats. See, Kobe and Deisenhofer, TrendsBiochem. Sci., 19(10):415-421 (October 1994).

A study has been reported on leucine-rich proteoglycans which serve astissue organizers, orienting and ordering collagen fibrils duringontogeny and are involved in pathological processes such as woundhealing, tissue repair, and tumor stroma formation. Iozzo, R. V., Crit.Rev. Biochem. Mol. Biol., 32(2):141-174 (1997). Others studiesimplicating leucine rich proteins in wound healing and tissue repair areDe La Salle, C., et al., Vouv. Rev. Fr. Hematol. (Germany),37(4):215-222 (1995), reporting mutations in the leucine rich motif in acomplex associated with the bleeding disorder Bernard-Soulier syndromeand Chlemetson, K. J., Thromb. Haemost. (Germany), 74(1):111-116 (July1995), reporting that platelets have leucine rich repeats. Anotherprotein of particular interest which has been reported to haveleucine-rich repeats is the SLIT protein which has been reported to beuseful in treating neuro-degenerative diseases such as Alzheimer'sdisease, nerve damage such as in Parkinson's disease, and for diagnosisof cancer, see, Artavanistsakonas, S. and Rothberg, J. M., WO9210518-A1by Yale University. Other studies reporting on the biological functionsof proteins having leucine-rich repeats include: Tayar, N., et al., Mol.Cell Endocrinol., (Ireland), 125(1-2):65-70 (December 1996)(gonadotropin receptor involvement); Miura, Y., et al., Nippon Rinsho(Japan), 54(7):1784-1789 (July 1996) (apoptosis involvement); Harris, P.C., et al., J. Am. Soc. Nephrol., 6(4):1125-1133 (October 1995) (kidneydisease involvement); and Ruoslahti, E. I., et al., WO9110727-A by LaJolla Cancer Research Foundation (decorin binding to transforming growthfactors involvement for treatment for cancer, wound healing andscarring).

Efforts are therefore being undertaken by both industry and academia toidentify new proteins having leucine rich repeats to better understandprotein-protein interactions. Of particular interest are those proteinshaving leucine rich repeats and homology to known neuronal leucine richrepeat proteins. Many efforts are focused on the screening of mammalianrecombinant DNA libraries to identify the coding sequences for novelsecreted and membrane-bound proteins having leucine rich repeats.Examples of screening methods and techniques are described in theliterature [see, for example, Klein et al., Proc. Natl. Acad. Sci.,93:7108-7113 (1996); U.S. Pat. No. 5,536,637)].

We describe herein the identification and characterization of a novelpolypeptide which has homology to leucine rich repeat proteins,designated herein as PRO293.

39. PRO247

Protein-protein interactions include receptor and antigen complexes andsignaling mechanisms. As more is known about the structural andfunctional mechanisms underlying protein-protein interactions,protein-protein interactions can be more easily manipulated to regulatethe particular result of the protein-protein interaction. Thus, theunderlying mechanisms of protein-protein interactions are of interest tothe scientific and medical community.

All proteins containing leucine-rich repeats are thought to be involvedin protein-protein interactions. Leucine-rich repeats are short sequencemotifs present in a number of proteins with diverse functions andcellular locations. The crystal structure of ribonuclease inhibitorprotein has revealed that leucine-rich repeats correspond to beta-alphastructural units. These units are arranged so that they form a parallelbeta-sheet with one surface exposed to solvent, so that the proteinacquires an unusual, nonglubular shape. These two features have beenindicated as responsible for the protein-binding functions of proteinscontaining leucine-rich repeats. See, Kobe and Deisenhofer, TrendsBiochem. Sci., 19(10):415-421 (October 1994).

A study has been reported on leucine-rich proteoglycans which serve astissue organizers, orienting and ordering collagen fibrils duringontogeny and are involved in pathological processes such as woundhealing, tissue repair, and tumor stroma formation. Iozzo, R. V., Crit.Rev. Biochem. Mol. Biol., 32(2):141-174 (1997). Others studiesimplicating leucine rich proteins in wound healing and tissue repair areDe La Salle, C., et al., Vouv. Rev. Fr. Hematol. (Germany),37(4):215-222 (1995), reporting mutations in the leucine rich motif in acomplex associated with the bleeding disorder Bernard-Soulier syndromeand Chlemetson, K. J., Thromb. Haemost. (Germany), 74(1):111-116 (July1995), reporting that platelets have leucine rich repeats. Anotherprotein of particular interest which has been reported to haveleucine-rich repeats is the SLIT protein which has been reported to beuseful in treating neuro-degenerative diseases such as Alzheimer'sdisease, nerve damage such as in Parkinson's disease, and for diagnosisof cancer, see, Artavanistsakonas, S. and Rothberg, J. M., WO9210518-A1by Yale University. Other studies reporting on the biological functionsof proteins having leucine-rich repeats include: Tayar, N., et al., Mol.Cell Endocrinol., (Ireland), 125(1-2):65-70 (December 1996)(gonadotropin receptor involvement); Miura, Y., et al., Nippon Rinsho(Japan), 54(7):1784-1789 (July 1996) (apoptosis involvement); Harris, P.C., et al., J. Am. Soc. Nephrol., 6(4):1125-1133 (October 1995) (kidneydisease involvement); and Ruoslahti, E. I., et al., WO9110727-A by LaJolla Cancer Research Foundation (decorin binding to transforming growthfactors involvement for treatment for cancer, wound healing andscarring).

Densin is a glycoprotein which has been isolated from the brain whichhas all the hallmarks of an adhesion molecule. It is highly concentratedat synaptic sites in the brain and is expressed prominently in dendriticprocesses in developing neurons. Densin has been characterized as amember of the O-linked sialoglycoproteins. Densin has relevance tomedically important processes such as regeneration. Given thephysiological importance of synaptic processes and cell adhesionmechanisms in vivo, efforts are currently being under taken to identifynew, native proteins which are involved in synaptic machinery and celladhesion. Densin is further described in Kennedy, M. B, Trends Neurosci.(England), 20(6):264 (1997) and Apperson, et al., J. Neurosci.,16(21):6839 (1996).

Efforts are therefore being undertaken by both industry and academia toidentify new proteins having leucine rich repeats to better understandprotein-protein interactions. Of particular interest are those proteinshaving leucine rich repeats and homology to known proteins havingleucine rich repeats such as KIAA0231 and densin. Many efforts arefocused on the screening of mammalian recombinant DNA libraries toidentify the coding sequences for novel secreted and membrane-boundproteins having leucine rich repeats. Examples of screening methods andtechniques are described in the literature [see, for example, Klein etal., Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No.5,536,637)].

We describe herein the identification and characterization of a novelpolypeptide which has homology to leucine rich repeat proteins,designated herein as PRO247.

40. PRO302, PRO303; PRO304, PRO307 and PRO343

Proteases are enzymatic proteins which are involved in a large number ofvery important biological processes in mammalian and non-mammalianorganisms. Numerous different protease enzymes from a variety ofdifferent mammalian and non-mammalian organisms have been bothidentified and characterized. The mammalian protease enzymes playimportant roles in many different biological processes including, forexample, protein digestion, activation, inactivation, or modulation ofpeptide hormone activity, and alteration of the physical properties ofproteins and enzymes.

In light of the important physiological roles played by proteaseenzymes, efforts are currently being undertaken by both industry andacademia to identify new, native protease homologs. Many of theseefforts are focused on the screening of mammalian recombinant DNAlibraries to identify the coding sequences for novel secreted andmembrane-bound receptor proteins. Examples of screening methods andtechniques are described in the literature [see, for example, Klein etal., Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No.5,536,637)]. We herein describe the identification of novel polypeptideshaving homology to various protease enzymes, designated herein asPRO302, PRO303, PRO304, PRO307 and PRO343 polypeptides.

41. PRO328

The GLIP protein family has been characterized as comprising zinc-fingerproteins which play important roles in embryogenesis. These proteins mayfunction as transcriptional regulatory proteins and are known to beamplified in a subset of human tumors. Glioma pathogenesis protein isstructurally related to a group of plant pathogenesis-related proteins.It is highly expressed in glioblastoma. See U.S. Pat. No. 5,582,981(issued Dec. 10, 1996) and U.S. Pat. No. 5,322,801 (issued Jun. 21,1996), Ellington, A. D. et al., Nature, 346:818 (1990), Grindley, J. C.et al., Dev. Biol., 188(2):337 (1997), Marine, J. C. et al., Mech. Dev.,63(2):211 (1997), The CRISP or cysteine rich secretory protein familyare a group of proteins which are also structurally related to a groupof plant pathogenesis proteins. [Schwidetzky, U., Biochem. J., 321:325(1997), Pfisterer, P., Mol. Cell Biol., 16(11):6160 (1996), Kratzschmar,J., Eur. J. Biochem., 236(3):827 (1996)]. We describe herein theidentification of a novel polypeptide which has homology to GLIP andCRISP, designated herein as PRO328 polypeptides.

42. PRO335, PRO331 and PRO326

Protein-protein interactions include receptor and antigen complexes andsignaling mechanisms. As more is known about the structural andfunctional mechanisms underlying protein-protein interactions,protein-protein interactions can be more easily manipulated to regulatethe particular result of the protein-protein interaction. Thus, theunderlying mechanisms of protein-protein interactions are of interest tothe scientific and medical community.

All proteins containing leucine-rich repeats are thought to be involvedin protein-protein interactions. Leucine-rich repeats are short sequencemotifs present in a number of proteins with diverse functions andcellular locations. The crystal structure of ribonuclease inhibitorprotein has revealed that leucine-rich repeats correspond to beta-alphastructural units. These units are arranged so that they form a parallelbeta-sheet with one surface exposed to solvent, so that the proteinacquires an unusual, nonglubular shape. These two features have beenindicated as responsible for the protein-binding functions of proteinscontaining leucine-rich repeats. See, Kobe and Deisenhofer, TrendsBiochem. Sci., 19(10):415-421 (October 1994).

A study has been reported on leucine-rich proteoglycans which serve astissue organizers, orienting and ordering collagen fibrils duringontogeny and are involved in pathological processes such as woundhealing, tissue repair, and tumor stroma formation. Iozzo, R. V., Crit.Rev. Biochem. Mol. Biol., 32(2):141-174 (1997). Others studiesimplicating leucine rich proteins in wound healing and tissue repair areDe La Salle, C., et al., Vouv. Rev. Fr. Hematol. (Germany),37(4):215-222 (1995), reporting mutations in the leucine rich motif in acomplex associated with the bleeding disorder Bernard-Soulier syndrome,Chlemetson, K. J., Thromb. Haemost. (Germany), 74(1): 111-116 (July1995), reporting that platelets have leucine rich repeats and Ruoslahti,E. I., et al., WO9110727-A by La Jolla Cancer Research Foundationreporting that decorin binding to transforming growth factorβ hasinvolvement in a treatment for cancer, wound healing and scarring.Related by function to this group of proteins is the insulin like growthfactor (IGF), in that it is useful in wound-healing and associatedtherapies concerned with re-growth of tissue, such as connective tissue,skin and bone; in promoting body growth in humans and animals; and instimulating other growth-related processes. The acid labile subunit ofIGF (ALS) is also of interest in that it increases the half-life of IGFand is part of the IGF complex in vivo.

Another protein which has been reported to have leucine-rich repeats isthe SLIT protein which has been reported to be useful in treatingneuro-degenerative diseases such as Alzheimer's disease, nerve damagesuch as in Parkinson's disease, and for diagnosis of cancer, see,Artavanistsakonas, S. and Rothberg, J. M., WO9210518-A1 by YaleUniversity. Of particular interest is LIG-1, a membrane glycoproteinthat is expressed specifically in glial cells in the mouse brain, andhas leucine rich repeats and immunoglobulin-like domains. Suzuki, etal., J. Biol. Chem. (U.S.), 271(37):22522 (1996). Other studiesreporting on the biological functions of proteins having leucine richrepeats include: Tayar, N., et al., Mol. Cell Endocrinol., (Ireland),125(1-2):65-70 (December 1996) (gonadotropin receptor involvement);Miura, Y., et al., Nippon Rinsho (Japan), 54(7): 1784-1789 (July 1996)(apoptosis involvement); Harris, P. C., et al., J. Am. Soc. Nephrol.,6(4):1125-1133 (October 1995) (kidney disease involvement).

Efforts are therefore being undertaken by both industry and academia toidentify new proteins having leucine rich repeats to better understandprotein-protein interactions. Of particular interest are those proteinshaving leucine rich repeats and homology to known proteins havingleucine rich repeats such as LIG-1, ALS and decorin. Many efforts arefocused on the screening of mammalian recombinant DNA libraries toidentify the coding sequences for novel secreted and membrane-boundproteins having leucine rich repeats. Examples of screening methods andtechniques are described in the literature [see, for example, Klein etal., Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No.5,536,637)].

We describe herein the identification and characterization of novelpolypeptides which have homology to proteins of the leucine rich repeatsuperfamily, designated herein as PRO335, PRO331 and PRO326polypeptides.

43. PRO332

Secreted proteins comprising a repeat characterized by an arrangement ofconserved leucine residues (leucine-rich repeat motif) have diversebiological roles. Certain proteoglycans, such as biglycan, fibromodulinand decorin, are, for example, characterized by the presence of aleucine-rich repeat of about 24 amino acids [Ruoslahti, Ann. Rev. Cell.Biol. 4 229-255 (1988); Oldberg et al., EMBO J. 8, 2601-2604 (1989)]. Ingeneral, proteoglycans are believed to play a role in regulatingextracellular matrix, cartilage or bone function. The proteoglycandecorin binds to collagen type I and II and affects the rate of fibrilformation. Fibromodulin also binds collagen and delays fibril formation.Both fibromodulin and decorin inhibit the activity of transforminggrowth factor beta (TGF-β) (U.S. Pat. No. 5,583,103 issued Dec. 10,1996). TGF-β is known to play a key role in the induction ofextracellular matrix and has been implicated in the development offibrotic diseases, such as cancer and glomerulonephritis. Accordingly,proteoglycans have been proposed for the treatment of fibrotic cancer,based upon their ability to inhibit TGF-β's growth stimulating activityon the cancer cell. Proteoglycans have also been described aspotentially useful in the treatment of other proliferative pathologies,including rheumatoid arthritis, arteriosclerosis, adult respiratorydistress syndrome, cirrhosis of the liver, fibrosis of the lungs,post-myocardial infarction, cardiac fibrosis, post-angioplastyrestenosis, renal interstitial fibrosis and certain dermal fibroticconditions, such as keloids and scarring, which might result from burninjuries, other invasive skin injuries, or cosmetic or reconstructivesurgery (U.S. Pat. No. 5,654,270, issued Aug. 5, 1997).

We describe herein the identification and characterization of novelpolypeptides which have homology to proteins of the leucine rich repeatsuperfamily, designated herein as PRO332 polypeptides.

44. PRO334

Microfibril bundles and proteins found in association with thesebundles, particularly attachment molecules, are of interest in the fieldof dermatology, particularly in the study of skin which has been damagedfrom aging, injuries or the sun. Fibrillin microfibrils define thecontinuous elastic network of skin, and are present in dermis asmicrofibril bundles devoid of measurable elastin extending from thedermal-epithelial junction and as components of the thick elastic fibrespresent in the deep reticular dermis. Moreover, Marfan syndrome has beenlinked to mutations which interfere with multimerization of fibrillinmonomers or other connective tissue elements.

Fibulin-1 is a modular glycoprotein with amino-terminalanaphlatoxin-like modules followed by nine epidermal growth factor(EGF)-like modules and, depending on alternative splicing, four possiblecarboxyl termini. Fibulin-2 is a novel extracellular matrix proteinfrequently found in close association with microfibrils containingeither fibronectin or fibrillin. Thus, fibrillin, fibulin, and moleculesrelated thereto are of interest, particularly for the use of preventingskin from being damaged from aging, injuries or the sun, or forrestoring skin damaged from same. Moreover, these molecules aregenerally of interest in the study of connective tissue and attachmentmolecules and related mechanisms. Fibrillin, fibulin and relatedmolecules are further described in Adams, et al., J. Mol. Biol.,272(2):226-36 (1997); Kielty and Shuttleworth, Microsc. Res. Tech.,38(4):413-27.(1997); and Child, J. Card. Surg,. 12(2Supp.):131-5 (1997).

Currently, efforts are being undertaken by both industry and academia toidentify new, native secreted and membrane-bound receptor proteins,particularly secreted proteins which have homology to fibulin andfibrillin. Many efforts are focused on the screening of mammalianrecombinant DNA libraries to identify the coding sequences for novelsecreted and membrane-bound receptor proteins. Examples of screeningmethods and techniques are described in the literature [see, forexample, Klein et al., Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S.Pat. No. 5,536,637)].

We herein describe the identification and characterization of novelpolypeptides having homology to fibulin and fibrillin, designated hereinas PRO334 polypeptides.

45. PRO346

The widespread occurrence of cancer has prompted the devotion ofconsiderable resources and discovering new treatments of treatment. Oneparticular method involves the creation of tumor or cancer specificmonoclonal antibodies (mAbs) which are specific to tumor antigens. SuchmAbs, which can distinguish between normal and cancerous cells areuseful in the diagnosis, prognosis and treatment of the disease.Particular antigens are known to be associated with neoplastic diseases,such as colorectal and breast cancer. Since colon cancer is a widespreaddisease, early diagnosis and treatment is an important medical goal.Diagnosis and treatment of cancer can be implemented using monoclonalantibodies (mABs) specific therefore having fluorescent, nuclearmagnetic or radioactive tags. Radioactive genes, toxins and/or drugtagged mAbs can be used for treatment in situ with minimal patientdescription.

Carcinoembryonic antigen (CEA) is a glycoprotein found in human coloncancer and the digestive organs of a 2-6 month human embryos. CEA is aknown human tumor marker and is widely used in the diagnosis ofneoplastic diseases, such as colon cancer. For example, when the serumlevels of CEA are elevated in a patient, a drop of CEA levels aftersurgery would indicate the tumor resection was successful. On the otherhand, a subsequent rise in serum CEA levels after surgery would indicatethat metastases of the original tumor may have formed or that newprimary tumors may have appeared. CEA may also be a target for mAb,antisense nucleotides

46. PRO268

Protein disulfide isomerase is an enzymatic protein which is involved inthe promotion of correct refolding of proteins through the establishmentof correct disulfide bond formation. Protein disulfide isomerase wasinitially identified based upon its ability to catalyze the renaturationof reduced denatured RNAse (Goldberger et al., J. Biol. Chem.239:1406-1410 (1964) and Epstein et al., Cold Spring Harbor Symp. Quant.Biol. 28:439-449 (1963)). Protein disulfide isomerase has been shown tobe a resident enzyme of the endoplasmic reticulum which is retained inthe endoplasmic reticulum via a -KDEL or -HDEL amino acid sequence atits C-terminus.

Given the importance of disulfide bond-forming enzymes and theirpotential uses in a number of different applications, for example inincreasing the yield of correct refolding of recombinantly produced eproteins, efforts are currently being undertaken by both industry andacademia to identify new, native proteins -having homology to proteindisulfide isomerase. Many of these efforts are focused on the screeningof mammalian recombinant DNA libraries to identify the coding sequencesfor novel protein disulfide isomerase homologs. We herein describe anovel polypeptide having homology to protein disulfide isomerase,designated herein as PRO268.

47. PRO330

Prolyl 4-hydroxylase is an enzyme which functions topost-translationally hydroxylate proline residues at the Y position ofthe amino acid sequence Gly-X-Y, which is a repeating three amino acidsequence found in both collagen and procollagen. Hydroxylation ofproline residues at the Y position of the Gly-X-Y amino acid triplet toform 4-hydroxyproline residues at those positions is required beforenewly synthesized collagen polypeptide chains may fold into their properthree-dimensional triple-helical conformation. If hydroxylation does notoccur, synthesized collagen polypeptides remain non-helical, are poorlysecreted by cells and cannot assemble into stable functional collagenfibrils. Vuorio et al., Proc. Natl. Acad. Sci. USA 89:7467-7470 (1992).Prolyl 4-hydroxylase is comprised of at least two different polypeptidesubunits, alpha and beta.

Efforts are being undertaken by both industry and academia to identifynew, native secreted and membrane-bound receptor proteins. Many effortsare focused on the screening of mammalian recombinant DNA libraries toidentify the coding sequences for novel secreted and membrane-boundreceptor proteins. Examples of screening methods and techniques aredescribed in the literature [see, for example, Klein et al., Proc. Natl.Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No. 5,536,637)]. Based uponthese efforts, Applicants have herein identified and describe a novelpolypeptide having homology to the alpha subunit of prolyl4-hydroxylase, designated herein as PRO330.

48. PRO339 and PRO310

Fringe is a protein which specifically blocks serrate-mediatedactivation of notch in the dorsal compartment of the Drosophila wingimaginal disc. Fleming, et al., Development, 124(15):2973-81 (1997).Therefore, fringe is of interest for both its role in development aswell as its ability to regulate serrate, particularly serrate'ssignaling abilities. Also of interest are novel polypeptides which mayhave a role in development and/or the regulation of serrate-likemolecules. Of particular interest are novel polypeptides having homologyto fringe as identified and described herein, designated herein asPRO339 and PRO310 polypeptides.

49. PRO244

Lectins are a class of proteins comprising a region that bindscarbohydrates specifically and non-covalently. Numerous lectins havebeen identified in higher animals, both membrane-bound and soluble, andhave been implicated in a variety of cell-recognition phenomena andtumor metastasis.

Most lectins can be classified as either C-type (calcium-dependent) orS-type (thiol-dependent).

Lectins are thought to play a role in regulating cellular events thatare initiated at the level of the plasma membrane. For example, plasmamembrane associated molecules are involved in the activation of varioussubsets of lymphoid cells, e.g. T-lymphocytes, and it is known that cellsurface molecules are responsible for activation of these cells andconsequently their response during an immune reaction.

A particular group of cell adhesion molecules, selecting, belong in thesuperfamily of C-type lectins. This group includes L-selectin(peripheral lymph node homing receptor (pnHR), LEC-CAM-1, LAM-1,gp90^(MEL), gp100^(MEL), gp110^(MEL), MEL-14 antigen, Leu-8 antigen,TQ-1 antigen, DREG antigen), E-selectin (LEC-CAM-2, LECAM-2, ELAM-1),and P-selectin (LEC-CAM-3, LECAM-3, GMP-140, PADGEM). The structure ofselectins consists of a C-type lectin (carbohydrate binding) domain, anepidermal growth factor-like (EGF-like) motif, and variable numbers ofcomplement regulatory (CR) motifs. Selectins are associated withleukocyte adhesion, e.g. the attachment of neutrophils to venularendothelial cells adjacent to inflammation (E-selectin), or with thetrafficking of lymphocytes from blood to secondary lymphoid organs, e.g.lymph nodes and Peyer's patches (L-selectin).

Another exemplary lectin is the cell-associated macrophage antigen,Mac-2 that is believed to be involved in cell adhesion and immuneresponses. Macrophages also express a lectin that recognizes Tn Ag, ahuman carcinoma-associated epitope.

Another C-type lectin is CD95 (Fas antigen/APO-1) that is an importantmediator of immunologically relevant regulated or programmed cell death(apoptosis). “Apoptosis” is a non-necrotic cell death that takes placein metazoan animal cells following activation of an intrinsic cellsuicide program. The cloning of Fas antigen is described in PCTpublication WO 91/10448, and European patent application EP510691. Themature Fas molecule consists of 319 amino acids of which 157 areextracellular, 17 constitute the transmembrane domain, and 145 areintracellular. Increased levels of Fas expression at T cell surface havebeen associated with tumor cells and HIV-infected cells. Ligation ofCD95 triggers apoptosis in the presence of interleukin-1 (IL-2).

C-type lectins also include receptors for oxidized low-densitylipoprotein (LDL). This suggests a possible role in the pathogenesis ofatherosclerosis.

We herein describe the identification and characterization of novelpolypeptides having homology to C-type lectins, designated herein asPRO244 polypeptides.

SUMMARY OF THE INVENTION

1. PRO211 and PRO217

Applicants have identified cDNA clones that encode novel polypeptideshaving homology to EGF, designated in the present application as“PRO211” and “PRO217” polypeptides.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO211 or PRO217 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding EGF-likehomologue PRO211 and PRO217 polypeptides of FIG. 2 (SEQ ID NO:2) and/or4 (SEQ ID NO:4) indicated in FIG. 1 (SEQ ID NO1) and/or FIG. 3 (SEQ IDNO:3), respectively, or is complementary to such encoding nucleic acidsequence, and remains stably bound to it under at least moderate, andoptionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO211 and PRO217EGF4like homologue PRO211 and PRO217 polypeptides. In particular, theinvention provides isolated native sequence PRO211 and PRO217 EGF-likehomologue polypeptides, which in one embodiment, includes an amino acidsequence comprising residues: 1 to 353 of FIG. 2 (SEQ ID NO:2) or (2) 1to 379 of FIG. 4 (SEQ ID NO: 4).

2. PRO230

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as “PRO230”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO230 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO230 polypeptidehaving amino acid residues 1 through 467 of FIG. 6 (SEQ ID NO:12), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO230polypeptide. In particular, the invention provides isolated nativesequence PRO230 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 through 467 of FIG. 6 (SEQ IDNO:12).

In another embodiment, the invention provides an expressed sequence tag(EST) comprising the nucleotide sequence of SEQ ID NO:13 (FIG. 7) whichis herein designated as DNA20088.

3. PRO232

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as “PRO232”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO232 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO232 polypeptidehaving amino acid residues 1 to 114 of FIG. 9 (SEQ ID NO:18), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO232polypeptide. In particular, the invention provides isolated nativesequence PRO232 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 114 of FIG. 9 (SEQ ID NO:18).

4. PRO187

Applicants have identified a cDNA clone that encodes a novelpolypeptide, designated in the present application as “PRO187”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO187 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO187 polypeptideof FIG. 11 (SEQ ID NO:23), or is complementary to such encoding nucleicacid sequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions. In another aspect, theinvention provides a nucleic acid comprising the coding sequence of FIG.10 (SEQ ID NO:22) or its complement. In another aspect, the inventionprovides a nucleic acid of the full length protein of cloneDNA27864-1155, deposited with the ATCC under accession number ATCC209375, alternatively the coding sequence of clone DNA27864-1155,deposited under accession number ATCC 209375.

In yet another embodiment, the invention provides isolated PRO187polypeptide. In particular, the invention provides isolated nativesequence PRO187 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 205 of FIG. 11 (SEQ ID NO:23).Alternatively, the invention provides a polypeptide encoded by thenucleic acid deposited under accession number ATCC 209375.

5. PRO265

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as “PRO265”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO265 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO265 polypeptidehaving amino acid residues 1 to 660 of FIG. 13 (SEQ ID NO:28), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO265polypeptide. In particular, the invention provides isolated nativesequence PRO265 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 660 of FIG. 13 (SEQ ID NO:28). Anadditional embodiment of the present invention is directed to anisolated extracellular domain of a PRO265 polypeptide.

6. PRO219

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as “PRO219”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO219 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO219 polypeptidehaving amino acid residues 1 to 915 of FIG. 15 (SEQ ID NO:34), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO219polypeptide. In particular, the invention provides isolated nativesequence PRO219 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 915 of FIG. 15 (SEQ ID NO:34).

7. PRO246

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as “PRO246”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO246 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO246 polypeptidehaving amino acid residues 1 to 390 of FIG. 17 (SEQ ID NO:39), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO246polypeptide. In particular, the invention provides isolated nativesequence PRO246 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 390 of FIG. 17 (SEQ ID NO:39). Anadditional embodiment of the present invention is directed to anisolated extracellular domain of a PRO246 polypeptide.

8. PRO228

Applicants have identified a cDNA clone that encodes a novel polypeptidehaving homology to CD97, EMR1 and latrophilin, wherein the polypeptideis designated in the present application as “PRO228”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO228 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO228 polypeptidehaving amino acid residues 1 to 690 of FIG. 19 (SEQ ID NO:49), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO228polypeptide. In particular, the invention provides isolated nativesequence PRO228 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 690 of FIG. 19 (SEQ ID NO:49). Anadditional embodiment of the present invention is directed to anisolated extracellular domain of a PRO228 polypeptide.

In another embodiment, the invention provides an expressed sequence tag(EST) comprising the nucleotide sequence of SEQ ID NO:50, designatedherein as DNA21951.

9. PRO533

Applicants have identified a cDNA clone (DNA49435-1219) that encodes anovel polypeptide, designated in the present application as PRO533.

In one embodiment, the invention provides an isolated nucleic acidmolecule having at least about 80% sequence identity to (a) a DNAmolecule encoding a PRO533 polypeptide comprising the sequence of aminoacids 23 to 216 of FIG. 22 (SEQ ID NO:59), or (b) the complement of theDNA molecule of (a). The sequence identity preferably is about 85%, morepreferably about 90%, most preferably about 95%. In one aspect, theisolated nucleic acid has at least about 80%, preferably at least about85%, more preferably at least about 90%, and most preferably at leastabout 95% sequence identity with a polypeptide having amino acidresidues 23 to 216 of FIG. 22 (SEQ ID NO:59). Preferably, the highestdegree of sequence identity occurs within the secreted portion (aminoacids 23 to 216 of FIG. 22, SEQ ID NO:59). In a further embodiment, theisolated nucleic acid molecule comprises DNA encoding a PRO533polypeptide having amino acid residues 1 to 216 of FIG. 22 (SEQ IDNO:59), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In another aspect, the inventionprovides a nucleic acid of the full length protein of cloneDNA49435-1219, deposited with the ATCC under accession number ATCC209480.

In yet another embodiment, the invention provides isolated PRO533polypeptide. In particular, the invention provides isolated nativesequence PRO533 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 23 to 216 of FIG. 22 (SEQ ID NO:59).Native PRO533 polypeptides with or without the native signal sequence(amino acids 1 to 22 in FIG. 22 (SEQ ID NO:59)), and with or without theinitiating methionine are specifically included. Alternatively, theinvention provides a PRO533 polypeptide encoded by the nucleic aciddeposited under accession number ATCC 209480.

10. PRO245

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as “PRO245”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO245 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO245 polypeptidehaving amino acid residues 1 to 312 of FIG. 24 (SEQ ID NO:64), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO245polypeptide. In particular, the invention provides isolated nativesequence PRO245 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 312 of FIG. 24 (SEQ ID NO:64).

11. PRO220, PRO221 and PRO227

Applicants have identified cDNA clones that each encode novelpolypeptides, all having leucine rich repeats. These polypeptides aredesignated in the present application as PRO220, PRO221 and PRO227.

In one embodiment, the invention provides isolated nucleic acidmolecules comprising DNA respectively encoding PRO220, PRO221 andPRO227, respectively. In one aspect, provided herein is an isolatednucleic acid comprises DNA encoding the PRO220 polypeptide having aminoacid residues 1 through 708 of FIG. 26 (SEQ ID NO:69), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions. Also provided herein is an isolated nucleic acidcomprises DNA encoding the PRO221 polypeptide having amino acid residues1 through 259 of FIG. 28 (SEQ ID NO:71), or is complementary to suchencoding nucleic acid sequence, and remains stably bound to it under atleast moderate, and optionally, under high stringency conditions.Moreover, also provided herein is an isolated nucleic acid comprises DNAencoding the PRO227 polypeptide having amino acid residues 1 through 620of FIG. 30 (SEQ ID NO:73), or is complementary to such encoding nucleicacid sequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO220, PRO221and PRO227 polypeptides. In particular, provided herein is the isolatednative sequence for the PRO220 polypeptide, which in one embodiment,includes an amino acid sequence comprising residues 1 to 708 of FIG. 26(SEQ ID NO:69). Additionally provided herein is the isolated nativesequence for the PRO221 polypeptide, which in one embodiment, includesan amino acid sequence comprising residues 1 to 259 of FIG. 28 (SEQ IDNO:71). Moreover, provided herein is the isolated native sequence forthe PRO227 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 1 to 620 of FIG. 30 (SEQ ID NO:73).

12. PRO258

Applicants have identified a cDNA clone that encodes a novel polypeptidehaving homology to CRTAM and poliovirus receptor precursors, wherein thepolypeptide is designated in the present application as “PRO258”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO258 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO258 polypeptidehaving amino acid residues 1 to 398 of FIG. 32 (SEQ ID NO:84), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO258polypeptide. In particular, the invention provides isolated nativesequence PRO258 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 398 of FIG. 32 (SEQ ID NO:84). Anadditional embodiment of the present invention is directed to anisolated extracellular domain of a PRO258 polypeptide.

13. PRO266

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as “PRO266”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO266 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO266 polypeptidehaving amino acid residues 1 to 696 of FIG. 34 (SEQ ID NO:91), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO266polypeptide. In particular, the invention provides isolated nativesequence PRO266 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 696 of FIG. 34 (SEQ ID NO:91).

14. PRO269

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as PRO269.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO269 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO269 polypeptidehaving amino acid residues 1 to 490 of FIG. 36 (SEQ ID NO:96), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO269polypeptide. In particular, the invention provides isolated nativesequence PRO269 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 490 of FIG. 36 (SEQ ID NO:96). Anadditional embodiment of the present invention is directed to anisolated extracellular domain of a PRO269 polypeptide.

15. PRO287

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as “PRO287”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO287 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO287 polypeptidehaving amino acid residues 1 to 415 of FIG. 38 (SEQ ID NO:104), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO287polypeptide. In particular, the invention provides isolated nativesequence PRO287 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 415 of FIG. 38 (SEQ ID NO:104).

16. PRO214

Applicants have identified a cDNA clone that encodes a novelpolypeptide, designated in the present application as “PRO214”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO214 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO214 polypeptideof FIG. 40 (SEQ ID NO:109), or is complementary to such encoding nucleicacid sequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions. In another aspect, theinvention provides a nucleic acid comprising the coding sequence of FIG.39 (SEQ ID NO:108) or its complement. In another aspect, the inventionprovides a nucleic acid of the full length protein of cloneDNA32286-1191, deposited with ATCC under accession number ATCC 209385.

In yet another embodiment, the invention provides isolated PRO214polypeptide. In particular, the invention provides isolated nativesequence PRO214 polypeptide, which in one embodiment, includes an aminoacid sequence comprising the residues of FIG. 40 (SEQ ID NO:109).Alternatively, the invention provides a polypeptide encoded by thenucleic acid deposited under accession number ATCC 209385.

17. PRO317

Applicants have identified a cDNA clone that encodes a novelpolypeptide, designated in the present application as “PRO317”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding PRO317 polypeptide. In one aspect, theisolated nucleic acid comprises DNA (SEQ ID NO:113) encoding PRO317polypeptide having amino acid residues 1 to 366 of FIG. 42, or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO317polypeptide. In particular, the invention provides isolatednative-sequence PRO317 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 366 of FIG. 42 (SEQ IDNO:114).

In yet another embodiment, the invention supplies a method of detectingthe presence of PRO317 in a sample, the method comprising:

a) contacting a detectable anti-PRO317 antibody with a sample suspectedof containing PRO317; and

b) detecting binding of the antibody to the sample; wherein the sampleis selected from the group consisting of a body fluid, a tissue sample,a cell extract, and a cell culture medium.

In a still further embodiment a method is provided for determining thepresence of PRO317 mRNA in a sample, the method comprising:

a) contacting a sample suspected of containing PRO317 mRNA with adetectable nucleic acid probe that hybridizes under moderate tostringent conditions to PRO317 mRNA; and

b) detecting hybridization of the probe to the sample.

Preferably, in this method the sample is a tissue sample and thedetecting step is by in situ hybridization, or the sample is a cellextract and detection is by Northern analysis.

Further, the invention provides a method for treating aPRO317-associated disorder comprising administering to a mammal aneffective amount of the PRO317 polypeptide or a composition thereofcontaining a carrier, or with an effective amount of a PRO317 agonist orPRO317 antagonist, such as an antibody which binds specifically toPRO317.

18. PRO301

Applicants have identified a cDNA clone (DNA40628-1216) that encodes anovel polypeptide, designated in the present application as “PRO301”.

In one embodiment, the invention provides an isolated nucleic acidmolecule having at least about 80% sequence identity to (a) a DNAmolecule encoding a PRO301 polypeptide comprising the sequence of aminoacids 28 to 258 of FIG. 44 (SEQ ID NO:119), or (b) the complement of theDNA molecule of (a). The sequence identity preferably is about 85%, morepreferably about 90%, most preferably about 95%. In one aspect, theisolated nucleic acid has at least about 80%, preferably at least about85%, more preferably at least about 90%, and most preferably at leastabout 95% sequence identity with a polypeptide having amino acidresidues 28 to 258 of FIG. 44 (SEQ ID NO:119). Preferably, the highestdegree of sequence identity occurs within the extracellular domains(amino acids 28 to 258 of FIG. 44, SEQ ID NO:119). In a furtherembodiment, the isolated nucleic acid molecule comprises DNA encoding aPRO301 polypeptide having amino acid residues 28 to 299 of FIG. 44 (SEQID NO:119), or is complementary to such encoding nucleic acid sequence,and remains stably bound to it under at least moderate, and optionally,under high stringency conditions. In another aspect, the inventionprovides a nucleic acid of the full length protein of cloneDNA40628-1216, deposited with the ATCC under accession number ATCC209432, alternatively the coding sequence of clone DNA40628-1216,deposited under accession number ATCC 209432.

In yet another embodiment, the invention provides isolated PRO301polypeptide. In particular, the invention provides isolated nativesequence PRO301 polypeptide, which in one embodiment, includes an aminoacid sequence comprising the extracellular domain residues 28 to 258 ofFIG. 44 (SEQ ID NO:119). Native PRO301 polypeptides with or without thenative signal sequence (amino acids 1 to 27 in FIG. 44 (SEQ ID NO:119),and with or without the initiating methionine are specifically included.Additionally, the sequences of the invention may also comprise thetransmembrane domain (residues 236 to about 258 in FIG. 44; SEQ IDNO:119) and/or the intracellular domain (about residue 259 to 299 inFIG. 44; SEQ ID NO:119). Alternatively, the invention provides a PRO301polypeptide encoded by the nucleic acid deposited under accession numberATCC 209432.

19. PRO224

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as “PRO224”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO224 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO224 polypeptidehaving amino acid residues 1 to 282 of FIG. 46 (SEQ ID NO:127), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO224polypeptide. In particular, the invention provides isolated nativesequence PRO224 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 282 of FIG. 46 (SEQ ID NO:127).

20. PRO222

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as “PRO222”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO222 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO222 polypeptidehaving amino acid residues 1 to 490 of FIG. 48 (SEQ ID NO:132), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO222polypeptide. In particular, the invention provides isolated nativesequence PRO222 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 490 of FIG. 48 (SEQ ID NO:132).

21. PRO234

Applicants have identified a cDNA clone that encodes a novel lectinpolypeptide molecule, designated in the present application as “PRO234”.

In one embodiment, the invention provides an isolated nucleic acidencoding a novel lectin comprising DNA encoding a PRO234 polypeptide. Inone aspect, the isolated nucleic acid comprises the DNA encoding PRO234polypeptides having amino acid residues 1 to 382 of FIG. 50 (SEQ IDNO:137), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In another aspect, the inventionprovides an isolated nucleic acid molecule comprising the nucleotidesequence of FIG. 49 (SEQ ID NO:136).

In another embodiment, the invention provides isolated novel PRO234polypeptides. In particular, the invention provides isolated nativesequence PRO234 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 382 of FIG. 50 (SEQ ID NO:137).

In yet another embodiment, the invention provides oligonucleotide probesuseful for isolating genomic and cDNA nucleotide sequences.

22. PRO231

Applicants have identified a cDNA clone that encodes a novel polypeptidehaving homology to a putative acid phosphatase, wherein the polypeptideis designated in the present application as “PRO231”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO231 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO231 polypeptidehaving amino acid residues 1 to 428 of FIG. 52 (SEQ ID NO:142), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO231polypeptide. In particular, the invention provides isolated nativesequence PRO231 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 428 of FIG. 52 (SEQ ID NO:142).

23. PRO229

Applicants have identified a cDNA clone that encodes a novel polypeptidehaving homology to scavenger receptors wherein the polypeptide isdesignated in the present application as “PRO229”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO229 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO229 polypeptidehaving amino acid residues 1 to 347 of FIG. 54 (SEQ ID NO:148), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO229polypeptide. In particular, the invention provides isolated nativesequence PRO229 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 347 of FIG. 54 (SEQ ID NO:148).

24. PRO238

Applicants have identified a cDNA clone that encodes a novel polypeptidehaving homology to reductase, wherein the polypeptide is designated inthe present application as “PRO238”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO238 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO238 polypeptidehaving amino acid residues 1 to 310 of FIG. 56 (SEQ ID NO:153), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO238polypeptide. In particular, the invention provides isolated nativesequence PRO238 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 310 of FIG. 56 (SEQ ID NO:153).

25. PRO233

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as “PRO233”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO233 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO233 polypeptidehaving amino acid residues 1 to 300 of FIG. 58 (SEQ ID NO:159), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO233polypeptide. In particular, the invention provides isolated nativesequence PRO233 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 300 of FIG. 58 (SEQ ID NO:159).

26. PRO223

Applicants have identified a cDNA clone that encodes a novel polypeptidehaving homology to serine carboxypeptidase polypeptides, wherein thepolypeptide is designated in the present application as “PRO223”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO223 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO223 polypeptidehaving amino acid residues 1 to 476 of FIG. 60 (SEQ ID NO:164), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO223polypeptide. In particular, the invention provides isolated nativesequence PRO223 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 476 of FIG. 60 (SEQ ID NO:164).

27. PRO235

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as “PRO235”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO235 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO235 polypeptidehaving amino acid residues 1 to 552 of FIG. 62 (SEQ ID NO:170), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO235polypeptide. In particular, the invention provides isolated nativesequence PRO235 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 552 of FIG. 62 (SEQ ID NO:170).

28. PRO236 and PRO262

Applicants have identified cDNA clones that encode novel polypeptideshaving homology to β-galactosidase, wherein those polypeptides aredesignated in the present application as “PRO236” and “PRO262”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO236 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO236 polypeptidehaving amino acid residues 1 to 636 of FIG. 64 (SEQ ID NO:175), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO262 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO262 polypeptidehaving amino acid residues 1 to 654 of FIG. 66 (SEQ ID NO:177), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO236polypeptide. In particular, the invention provides isolated nativesequence PRO236 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 636 of FIG. 64 (SEQ ID NO:175).

In another embodiment, the invention provides isolated PRO262polypeptide. In particular, the invention provides isolated nativesequence PRO262 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 654 of FIG. 66 (SEQ ID NO:177).

29. PRO239

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as “PRO239”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO239 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO239 polypeptidehaving amino acid residues 1 to 501 of FIG. 68 (SEQ ID NO:185), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO239polypeptide. In particular, the invention provides isolated nativesequence PRO239 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 501 of FIG. 68 (SEQ ID NO:185).

30. PRO257

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as “PRO257”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO257 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO257 polypeptidehaving amino acid residues 1 to 607 of FIG. 70 (SEQ ID NO:190), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO257polypeptide. In particular, the invention provides isolated nativesequence PRO257 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 607 of FIG. 70 (SEQ ID NO:190).An additional embodiment of the present invention is directed to anisolated extracellular domain of a PRO257 polypeptide.

31. PRO260

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as “PRO260”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO260 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO260 polypeptidehaving amino acid residues 1 to 467 of FIG. 72 (SEQ ID NO:195), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO260polypeptide. In particular, the invention provides isolated nativesequence PRO260 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 467 of FIG. 72 (SEQ ID NO:195).

32. PRO263

Applicants have identified a cDNA clone that encodes a novel polypeptidehaving homology to CD44 antigen, wherein the polypeptide is designatedin the present application as “PRO263”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO263 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO263 polypeptidehaving amino acid residues 1 to 322 of FIG. 74 (SEQ ID NO:201), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO263polypeptide. In particular, the invention provides isolated nativesequence PRO263 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 322 of FIG. 74 (SEQ ID NO:201).An additional embodiment of the present invention is directed to anisolated extracellular domain of a PRO263 polypeptide.

33. PRO270

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as “PRO270”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO270 polypeptide. In one aspect,the isolated nucleic acid comprises DNA which includes the sequenceencoding the PRO270 polypeptide having amino acid residues 1 to 296 ofFIG. 76 (SEQ ID NO:207), or is complementary to such encoding nucleicacid sequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO270polypeptide. In particular, the invention provides isolated nativesequence PRO270 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 296 of FIG. 76 (SEQ ID NO:207).

34. PRO271

Applicants have identified a cDNA clone that encodes a novel polypeptidehaving homology to the proteoglycan link protein, wherein thepolypeptide is designated in the present application as “PRO271”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO271 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO271 polypeptidehaving amino acid residues 1 to 360 of FIG. 78 (SEQ ID NO:213), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO271polypeptide. In particular, the invention provides isolated nativesequence PRO271 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 360 of FIG. 78 (SEQ ID NO:213).

35. PRO272

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as “PRO272”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO272 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO272 polypeptidehaving amino acid residues 1 to 328 of FIG. 80 (SEQ ID NO:221), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO272polypeptide. In particular, the invention provides isolated nativesequence PRO272 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 328 of FIG. 80 (SEQ ID NO:211).

36. PRO294

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as “PRO294”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO294 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO294 polypeptidehaving amino acid residues 1 to 550 of FIG. 82 (SEQ ID NO:227), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO294polypeptide. In particular, the invention provides isolated nativesequence PRO294 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 550 of FIG. 82 (SEQ ID NO:227).

37. PRO295

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as “PRO295”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO295 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO295 polypeptidehaving amino acid residues 1 to 350 of FIG. 84 (SEQ ID NO:236), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO295polypeptide. In particular, the invention provides isolated nativesequence PRO295 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 350 of FIG. 84 (SEQ ID NO:236).

38. PRO293

Applicants have identified a cDNA clone that encodes a novel humanneuronal leucine rich repeat polypeptide, wherein the polypeptide isdesignated in the present application as “PRO293”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO293 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO293 polypeptidehaving amino acid residues 1 to 713 of FIG. 86 (SEQ ID NO:245), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO293polypeptide. In particular, the invention provides isolated nativesequence PRO293 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 713 of FIG. 86 (SEQ ID NO:245).An additional embodiment of the present invention is directed to anisolated extracellular domain of a PRO293 polypeptide.

39. PRO247

Applicants have identified a cDNA clone that encodes a novel polypeptidehaving leucine rich repeats wherein the polypeptide is designated in thepresent application as “PRO247”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO247 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO247 polypeptidehaving amino acid residues 1 to 546 of FIG. 88 (SEQ ID NO:250), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO247polypeptide. In particular, the invention provides isolated nativesequence PRO247 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 546 of FIG. 88 (SEQ ID NO:250).An additional embodiment of the present invention is directed to anisolated extracellular domain of a PRO247 polypeptide.

40. PRO302, PRO303, PRO304, PRO307 and PRO343

Applicants have identified cDNA clones that encode novel polypeptideshaving homology to various proteases, wherein those polypeptide aredesignated in the present application as “PRO302”, “PRO303”, “PRO304”,“PRO307” and “PRO343” polypeptides.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO302 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO302 polypeptidehaving amino acid residues 1 to 452 of FIG. 90 (SEQ ID NO:255), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO303 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO303 polypeptidehaving amino acid residues 1 to 314 of FIG. 92 (SEQ ID NO:257), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In yet another embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO304 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO304polypeptide having amino acid residues 1 to 556 of FIG. 94 (SEQ IDNO:259), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions.

In another embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO307 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO307 polypeptidehaving amino acid residues 1 to 383 of FIG. 96 (SEQ ID NO:261), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO343 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO343 polypeptidehaving amino acid residues 1 to 317 of FIG. 98 (SEQ ID NO:263), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO302polypeptide. In particular, the invention provides isolated nativesequence PRO302 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 452 of FIG. 90 (SEQ ID NO:255).

In another embodiment, the invention provides isolated PRO303polypeptide. In particular, the invention provides isolated nativesequence PRO303 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 314 of FIG. 92 (SEQ ID NO:257).

In another embodiment, the invention provides isolated PRO304polypeptide. In particular, the invention provides isolated nativesequence PRO304 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 556 of FIG. 94 (SEQ ID NO:259).

In another embodiment, the invention provides isolated PRO307polypeptide. In particular, the invention provides isolated nativesequence PRO307 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 383 of FIG. 96 (SEQ ID NO:261).

In another embodiment, the invention provides isolated PRO343polypeptide. In particular, the invention provides isolated nativesequence PRO343 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 317 of FIG. 98 (SEQ ID NO:263).

41. PRO328

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as “PRO328”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO328 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO328 polypeptidehaving amino acid residues 1 to 463 of FIG. 100 (SEQ ID NO:285), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO328polypeptide. In particular, the invention provides isolated nativesequence PRO328 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 463 of FIG. 100 (SEQ ID NO:285).An additional embodiment of the present invention is directed to anisolated extracellular domain of a PRO306 polypeptide.

42. PRO335, PRO331 and PRO326

Applicants have identified three cDNA clones that respectively encodethree novel polypeptides, each having leucine rich repeats and homologyto LIG-1 and ALS. These polypeptides are designated in the presentapplication as PRO335, PRO331 and PRO326, respectively.

In one embodiment, the invention provides three isolated nucleic acidmolecules comprising DNA respectively encoding PRO335, PRO331 andPRO326, respectively. In one aspect, herein is provided an isolatednucleic acid comprising DNA encoding the PRO335 polypeptide having aminoacid residues 1 through 1059 of FIG. 102 (SEQ ID NO:290), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions. Also provided herein is an isolated nucleic acidcomprises DNA encoding the PRO331 polypeptide having amino acid residues1 through 640 of FIG. 104 (SEQ ID NO:292), or is complementary to suchencoding nucleic acid sequence, and remains stably bound to it under atleast moderate, and optionally, under high stringency conditions.Additionally provided herein is an isolated nucleic acid comprises DNAencoding the PRO326 polypeptide having amino acid residues 1 through1119 of FIG. 106 (SEQ ID NO:294), or is complementary to such encodingnucleic acid sequence, and remains stably bound to it under at leastmoderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO335, PRO331and PRO326 polypeptides or extracellular domains thereof. In particular,the invention provides isolated native sequence for the PRO335polypeptide, which in one embodiment, includes an amino acid sequencecomprising residues 1 through 1059 of FIG. 102 (SEQ ID NO:290). Alsoprovided herein is the isolated native sequence for the PRO331polypeptide, which in one embodiment, includes an amino acid sequencecomprising residues 1 through 640 of FIG. 104 (SEQ ID NO:292). Alsoprovided herein is the isolated native sequence for the PRO326polypeptide, which in one embodiment, includes an amino acid sequencecomprising residues 1 through 1119 of FIG. 106 (SEQ ID NO:294).

43. PRO332

Applicants have identified a cDNA clone (DNA40982-1235) that encodes anovel polypeptide, designated in the present application as “PRO332.”

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identity to(a) a DNA molecule encoding a PRO358 polypeptide comprising the sequenceof amino acids 49 to 642 of FIG. 108 (SEQ ID NO:310), or (b) thecomplement of the DNA molecule of (a). The sequence identity preferablyis about 85%, more preferably about 90%, most preferably about 95%. Inone aspect, the isolated nucleic acid has at least about 80%, preferablyat least about 85%, more preferably at least about 90%, and mostpreferably at least about 95% sequence identity with a polypeptidehaving amino acid residues 1 to 642 of FIG. 108 (SEQ ID NO:310).Preferably, the highest degree of sequence identity occurs within theleucine-rich repeat domains (amino acids 116 to 624 of FIG. 108, SEQ IDNO:310). In a further embodiment, the isolated nucleic acid moleculecomprises DNA encoding a PRO332 polypeptide having amino acid residues49 to 642 of FIG. 108 (SEQ ID NO:310), or is complementary to suchencoding nucleic acid sequence, and remains stably bound to it under atleast moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO332polypeptides. In particular, the invention provides isolated nativesequence PRO332 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 49 to 624 of FIG. 108 (SEQ ID NO:310).Native PRO332 polypeptides with or without the native signal sequence(amino acids 1 to 48 in FIG. 108, SEQ ID NO:310), and with or withoutthe initiating methionine are specifically included.

44. PRO334

Applicants have identified a cDNA clone that encodes a novel polypeptidehaving homology to fibulin and fibrillin, wherein the polypeptide isdesignated in the present application as “PRO334”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO334 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO334 polypeptidehaving amino acid residues 1 to 509 of FIG. 110 (SEQ ID NO:315), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO334polypeptide. In particular, the invention provides isolated nativesequence PRO334 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 509 of FIG. 110 (SEQ ID NO:315).

45. PRO346

Applicants have identified a cDNA clone (DNA44167-1243) that encodes anovel polypeptide, designated in the present application as “PRO346.”

In one embodiment, the invention provides an isolated nucleic acidmolecule having at least about 80% sequence identity to (a) a DNAmolecule encoding a PRO346 polypeptide comprising the sequence of aminoacids 19 to 339 of FIG. 112 (SEQ ID NO:320), or (b) the complement ofthe DNA molecule of (a). The sequence identity preferably is about 85%,more preferably about 90%, most preferably about 95%. In one aspect, theisolated nucleic acid has at least about 80%, preferably at least about85%, more preferably at least about 90%, and most preferably at leastabout 95% sequence identity with a polypeptide having amino acidresidues 19 to 339 of FIG. 112 (SEQ ID NO:320). Preferably, the highestdegree of sequence identity occurs within the extracellular domains(amino acids 19 to 339 of FIG. 112, SEQ ID NO:320). In alternativeembodiments, the polypeptide by which the homology is measured comprisesthe residues 1-339, 19-360 or 19-450 of FIG. 112, SEQ ID NO:320). In afurther embodiment, the isolated nucleic acid molecule comprises DNAencoding a PRO346 polypeptide having amino acid residues 19 to 339 ofFIG. 112 (SEQ ID NO:320), alternatively residues 1-339, 19-360 or 19-450of FIG. 112 (SEQ ID NO:320) or is complementary to such encoding nucleicacid sequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions. In another aspect, theinvention provides a nucleic acid of the full length protein of cloneDNA44167-1243, deposited with the ATCC under accession number ATCC209434, alternatively the coding sequence of clone DNA44167-1243,deposited under accession number ATCC 209434.

In yet another embodiment, the invention provides isolated PRO346polypeptide. In particular, the invention provides isolated nativesequence PRO346 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 19 to 339 of FIG. 112 (SEQ ID NO:320).Native PRO346 polypeptides with or without the native signal sequence(residues 1 to 18 in FIG. 112 (SEQ ID NO:320), with or without theinitiating methionine, with or without the transmembrane domain(residues 340 to 360) and with or without the intracellular domain(residues 361 to 450) are specifically included. Alternatively, theinvention provides a PRO346 polypeptide encoded by the nucleic aciddeposited under accession number ATCC 209434.

46. PRO268

Applicants have identified a cDNA clone that encodes a novel polypeptidehaving homology to protein disulfide isomerase, wherein the polypeptideis designated in the present application as “PRO268”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO268 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO268 polypeptidehaving amino acid residues 1 to 280 of FIG. 114 (SEQ ID NO:325), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO268polypeptide. In particular, the invention provides isolated nativesequence PRO268 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 280 of FIG. 114 (SEQ ID NO:325).An additional embodiment of the present invention is directed to anisolated extracellular domain of a PRO268 polypeptide.

47. PRO330

Applicants have identified a cDNA clone that encodes a novel polypeptidehaving homology to the alpha subunit of prolyl 4-hydroxylase, whereinthe polypeptide is designated in the present application as “PRO330”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO330 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding the PRO330 polypeptidehaving amino acid residues 1 to 533 of FIG. 116 (SEQ ID NO:332), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO330polypeptide. In particular, the invention provides isolated nativesequence PRO330 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 533 of FIG. 116 (SEQ ID NO:332).

48. PRO339 and PRO310

Applicants have identified two cDNA clones wherein each clone encodes anovel polypeptide having homology to fringe, wherein the polypeptidesare designated in the present application as “PRO339” and “PRO310”.

In one embodiment, the invention provides isolated nucleic acidmolecules comprising DNA encoding a PRO339 and/or a PRO310 polypeptide.In one aspect, the isolated nucleic acid comprises DNA encoding thePRO339 polypeptide having amino acid residues 1 to 772 of FIG. 118 (SEQID NO:339), or is complementary to such encoding nucleic acid sequence,and remains stably bound to it under at least moderate, and optionally,under high stringency conditions. In another aspect, the isolatednucleic acid comprises DNA encoding the PRO310 polypeptide having aminoacid residues 1 to 318 of FIG. 120 (SEQ ID NO:341), or is complementaryto such encoding nucleic acid sequence, and remains stably bound to itunder at least moderate, and optionally, under high stringencyconditions.

In another embodiment, the invention provides isolated PRO339 as well asisolated PRO310 polypeptides. In particular, the invention providesisolated native sequence PRO339 polypeptide, which in one embodiment,includes an amino acid sequence comprising residues 1 to 772 of FIG. 118(SEQ ID NO:339). The invention further provides isolated native sequencePRO310 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 1 to 318 of FIG. 120 (SEQ ID NO:341).

49. PRO244

Applicants have identified a cDNA clone that encodes a novelpolypeptide, designated in the present application as “PRO244”.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding PRO244 polypeptide. In one aspect, theisolated nucleic acid comprises DNA encoding PRO244 polypeptide havingamino acid residues 1 to 219 of FIG. 122 (SEQ ID NO:377), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions.

In another embodiment, the invention provides isolated PRO244polypeptide. In particular, the invention provides isolated nativesequence PRO244 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 219 of FIG. 122 (SEQ ID NO:377).

50. Additional Embodiments

In other embodiments of the present invention, the invention providesvectors comprising DNA encoding any of the herein describedpolypeptides. Host cell comprising any such vector are also provided. Byway of example, the host cells may be CHO cells, E. coli, or yeast. Aprocess for producing any of the herein described polypeptides isfurther provided and comprises culturing host cells under conditionssuitable for expression of the desired polypeptide and recovering thedesired polypeptide from the cell culture.

In other embodiments, the invention provides chimeric moleculescomprising any of the herein described polypeptides fused to aheterologous polypeptide or amino acid sequence. Example of suchchimeric molecules comprise any of the herein described polypeptidesfused to an epitope tag sequence or a Fc region of an immunoglobulin.

In another embodiment, the invention provides an antibody whichspecifically binds to any of the above or below described polypeptides.Optionally, the antibody is a monoclonal antibody, humanized antibody,antibody fragment or single-chain antibody.

In yet other embodiments, the invention provides oligonucleotide probesuseful for isolating genomic and cDNA nucleotide sequences, whereinthose probes may be derived from any of the above or below describednucleotide sequences.

In other embodiments, the invention provides an isolated nucleic acidmolecule comprising a nucleotide sequence that encodes a PROpolypeptide.

In one aspect, the isolated nucleic acid molecule comprises a nucleotidesequence having at least about 80% sequence identity, preferably atleast about 81% sequence identity, more preferably at least about 82%sequence identity, yet more preferably at least about 83% sequenceidentity, yet more preferably at least about 84% sequence identity, yetmore preferably at least about 85% sequence identity, yet morepreferably at least about 86% sequence identity, yet more preferably atleast about 87% sequence identity, yet more preferably at least about88% sequence identity, yet more preferably at least about 89% sequenceidentity, yet more preferably at least about 90% sequence identity, yetmore preferably at least about 91% sequence identity, yet morepreferably at least about 92% sequence identity, yet more preferably atleast about 93% sequence identity, yet more preferably at least about94% sequence identity, yet more preferably at least about 95% sequenceidentity, yet more preferably at least about 96% sequence identity, yetmore preferably at least about 97% sequence identity, yet morepreferably at least about 98% sequence identity and yet more preferablyat least about 99% sequence identity to (a) a DNA molecule encoding aPRO polypeptide having a full-length amino acid sequence as disclosedherein, an amino acid sequence lacking the signal peptide as disclosedherein or an extracellular domain of a transmembrane protein, with orwithout the signal peptide, as disclosed herein, or (b) the complementof the DNA molecule of (a).

In other aspects, the isolated nucleic acid molecule comprises anucleotide sequence having at least about 80% sequence identity,preferably at least about 81% sequence identity, more preferably atleast about 82% sequence identity, yet more preferably at least about83% sequence identity, yet more preferably at least about 84% sequenceidentity, yet more preferably at least about 85% sequence identity, yetmore preferably at least about 86% sequence identity, yet morepreferably at least about 87% sequence identity, yet more preferably atleast about 88% sequence identity, yet more preferably at least about89% sequence identity, yet more preferably at least about 90% sequenceidentity, yet more preferably at least about 91% sequence identity, yetmore preferably at least about 92% sequence identity, yet morepreferably at least about 93% sequence identity, yet more preferably atleast about 94% sequence identity, yet more preferably at least about95% sequence identity, yet more preferably at least about 96% sequenceidentity, yet more preferably at least about 97% sequence identity, yetmore preferably at least about 98% sequence identity and yet morepreferably at least about 99% sequence identity to (a) a DNA moleculecomprising the coding sequence of a full-length PRO polypeptide cDNA asdisclosed herein, the coding sequence of a PRO polypeptide lacking thesignal peptide as disclosed herein or the coding sequence of anextracellular domain of a transmembrane PRO polypeptide, with or withoutthe signal peptide, as disclosed herein, or (b) the complement of theDNA molecule of (a).

In a further aspect, the invention concerns an isolated nucleic acidmolecule comprising a nucleotide sequence having at least about 80%sequence identity, preferably at least about 81% sequence identity, morepreferably at least about 82% sequence identity, yet more preferably atleast about 83% sequence identity, yet more preferably at least about84% sequence identity, yet more preferably at least about 85% sequenceidentity, yet more preferably at least about 86% sequence identity, yetmore preferably at least about 87% sequence identity, yet morepreferably at least about 88% sequence identity, yet more preferably atleast about 89% sequence identity, yet more preferably at least about90% sequence identity, yet more preferably at least about 91% sequenceidentity, yet more preferably at least about 92% sequence identity, yetmore preferably at least about 93% sequence identity, yet morepreferably at least about 94% sequence identity, yet more preferably atleast about 95% sequence identity, yet more preferably at least about96% sequence identity, yet more preferably at least about 97% sequenceidentity, yet more preferably at least about 98% sequence identity andyet more preferably at least about 99% sequence identity to (a) a DNAmolecule that encodes the same mature polypeptide encoded by any of thehuman protein cDNAs deposited with the ATCC as disclosed herein, or (b)the complement of the DNA molecule of (a).

Another aspect the invention provides an isolated nucleic acid moleculecomprising a nucleotide sequence encoding a PRO polypeptide which iseither transmembrane domain-deleted or transmembrane domain-inactivated,or is complementary to such encoding nucleotide sequence, wherein thetransmembrane domain(s) of such polypeptide are disclosed herein.Therefore, soluble extracellular domains of the herein described PROpolypeptides are contemplated.

Another embodiment is directed to fragments of a PRO polypeptide codingsequence, or the complement thereof, that may find use as, for example,hybridization probes or for encoding fragments of a PRO polypeptide thatmay optionally encode a polypeptide comprising a binding site for ananti-PRO antibody. Such nucleic acid fragments are usually at leastabout 20 nucleotides in length, preferably at least about 30 nucleotidesin length, more preferably at least about 40 nucleotides in length, yetmore preferably at least about 50 nucleotides in length, yet morepreferably at least about 60 nucleotides in length, yet more preferablyat least about 70 nucleotides in length, yet more preferably at leastabout 80 nucleotides in length, yet more preferably at least about 90nucleotides in length, yet more preferably at least about 100nucleotides in length, yet more preferably at least about 110nucleotides in length, yet more preferably at least about 120nucleotides in length, yet more preferably at least about 130nucleotides in length, yet more preferably at least about 140nucleotides in length, yet more preferably at least about 150nucleotides in length, yet more preferably at least about 160nucleotides in length, yet more preferably at least about 170nucleotides in length, yet more preferably at least about 180nucleotides in length, yet more preferably at least about 190nucleotides in length, yet more preferably at least about 200nucleotides in length, yet more preferably at least about 250nucleotides in length, yet more preferably at least about 300nucleotides in length, yet more preferably at least about 350nucleotides in length, yet more preferably at least about 400nucleotides in length, yet more preferably at least about 450nucleotides in length, yet more preferably at least about 500nucleotides in length, yet more preferably at least about 600nucleotides in length, yet more preferably at least about 700nucleotides in length, yet more preferably at least about 800nucleotides in length, yet more preferably at least about 900nucleotides in length and yet more preferably at least about 1000nucleotides in length, wherein in this context the term “about” meansthe referenced nucleotide sequence length plus or minus 10% of thatreferenced length. It is noted that novel fragments of a PROpolypeptide-encoding nucleotide sequence may be determined in a routinemanner by aligning the PRO polypeptide-encoding nucleotide sequence withother known nucleotide sequences using any of a number of well knownsequence alignment programs and determining which PROpolypeptide-encoding nucleotide sequence fragment(s) are novel. All ofsuch PRO polypeptide-encoding nucleotide sequences are contemplatedherein. Also contemplated are the PRO polypeptide fragments encoded bythese nucleotide molecule fragments, preferably those PRO polypeptidefragments that comprise a binding site for an anti-PRO antibody.

In another embodiment, the invention provides isolated PRO polypeptideencoded by any of the isolated nucleic acid sequences hereinaboveidentified.

In a certain aspect, the invention concerns an isolated PRO polypeptide,comprising an amino acid sequence having at least about 80% sequenceidentity, preferably at least about 81% sequence identity, morepreferably at least about 82% sequence identity, yet more preferably atleast about 83% sequence identity, yet more preferably at least about84% sequence identity, yet more preferably at least about 85% sequenceidentity, yet more preferably at least about 86% sequence identity, yetmore preferably at least about 87% sequence identity, yet morepreferably at least about 88% sequence identity, yet more preferably atleast about 89% sequence identity, yet more preferably at least about90% sequence identity, yet more preferably at least about 91% sequenceidentity, yet more preferably at least about 92% sequence identity, yetmore preferably at least about 93% sequence identity, yet morepreferably at least about 94% sequence identity, yet more preferably atleast about 95% sequence identity, yet more preferably at least about96% sequence identity, yet more preferably at least about 97% sequenceidentity, yet more preferably at least about 98% sequence identity andyet more preferably at least about 99% sequence identity to a PROpolypeptide having a full-length amino acid sequence as disclosedherein, an amino acid sequence lacking the signal peptide as disclosedherein or an extracellular domain of a transmembrane protein, with orwithout the signal peptide, as disclosed herein.

In a further aspect, the invention concerns an isolated PRO polypeptidecomprising an amino acid sequence having at least about 80% sequenceidentity, preferably at least about 81% sequence identity, morepreferably at least about 82% sequence identity, yet more preferably atleast about 83% sequence identity, yet more preferably at least about84% sequence identity, yet more preferably at least about 85% sequenceidentity, yet more preferably at least about 86% sequence identity, yetmore preferably at least about 87% sequence identity, yet morepreferably at least about 88% sequence identity, yet more preferably atleast about 89% sequence identity, yet more preferably at least about90% sequence identity, yet more preferably at least about 91% sequenceidentity, yet more preferably at least about 92% sequence identity, yetmore preferably at least about 93% sequence identity, yet morepreferably at least about 94% sequence identity, yet more preferably atleast about 95% sequence identity, yet more preferably at least about96% sequence identity, yet more preferably at least about 97% sequenceidentity, yet more preferably at least about 98% sequence identity andyet more preferably at least about 99% sequence identity to an aminoacid sequence encoded by any of the human protein cDNAs deposited withthe ATCC as disclosed herein.

In a further aspect, the invention concerns an isolated PRO polypeptidecomprising an amino acid sequence scoring at least about 80% positives,preferably at least about 81% positives, more preferably at least about82% positives, yet more preferably at least about 83% positives, yetmore preferably at least about 84% positives, yet more preferably atleast about 85% positives, yet more preferably at least about 86%positives, yet more preferably at least about 87% positives, yet morepreferably at least about 88% positives, yet more preferably at leastabout 89% positives, yet more preferably at least about 90% positives,yet more preferably at least about 91% positives, yet more preferably atleast about 92% positives, yet more preferably at least about 93%positives, yet more preferably at least about 94% positives, yet morepreferably at least about 95% positives, yet more preferably at leastabout 96% positives, yet more preferably at least about 97% positives,yet more preferably at least about 98% positives and yet more preferablyat least about 99% positives when compared with the amino acid sequenceof a PRO polypeptide having a full-length amino acid sequence asdisclosed herein, an amino acid sequence lacking the signal peptide asdisclosed herein or an extracellular domain of a transmembrane protein,with or without the signal peptide, as disclosed herein.

In a specific aspect, the invention provides an isolated PRO polypeptidewithout the N-terminal signal sequence and/or the initiating methionineand is encoded by a nucleotide sequence that encodes such an amino acidsequence as hereinbefore described. Processes for producing the same arealso herein described, wherein those processes comprise culturing a hostcell comprising a vector which comprises the appropriate encodingnucleic acid molecule under conditions suitable for expression of thePRO polypeptide and recovering the PRO polypeptide from the cellculture.

Another aspect the invention provides an isolated PRO polypeptide whichis either transmembrane domain-deleted or transmembranedomain-inactivated. Processes for producing the same are also hereindescribed, wherein those processes comprise culturing a host cellcomprising a vector which comprises the appropriate encoding nucleicacid molecule under conditions suitable for expression of the PROpolypeptide and recovering the PRO polypeptide from the cell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO polypeptide as defined herein. In aparticular embodiment, the agonist or antagonist is an anti-PRO antibodyor a small molecule.

In a further embodiment, the invention concerns a method of identifyingagonists or antagonists to a PRO polypeptide which comprise contactingthe PRO polypeptide with a candidate molecule and monitoring abiological activity mediated by said PRO polypeptide. Preferably, thePRO polypeptide is a native PRO polypeptide.

In a still further embodiment, the invention concerns a composition ofmatter comprising a PRO polypeptide, or an agonist or antagonist of aPRO polypeptide as herein described, or an anti-PRO antibody, incombination with a carrier. Optionally, the carrier is apharmaceutically acceptable carrier.

Another embodiment of the present invention is directed to the use of aPRO polypeptide, or an agonist or antagonist thereof as hereinbeforedescribed, or an anti-PRO antibody, for the preparation of a medicamentuseful in the treatment of a condition which is responsive to the PROpolypeptide, an agonist or antagonist thereof or an anti-PRO antibody.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a nucleotide sequence (SEQ ID NO:1) of a native sequencePRO211 cDNA, wherein SEQ ID NO:1 is a clone designated herein as“DNA32292-1131”.

FIG. 2 shows the amino acid sequence (SEQ ID NO:2) derived from thecoding sequence of SEQ ID NO:1 shown in FIG. 1.

FIG. 3 shows a nucleotide sequence (SEQ ID NO:3) of a native sequencePRO217 cDNA, wherein SEQ ID NO:3 is a clone designated herein as“DNA33094-1131”.

FIG. 4 shows the amino acid sequence (SEQ ID NO:4) derived from thecoding sequence of SEQ ID NO:3 shown in FIG. 3.

FIG. 5 shows a nucleotide sequence (SEQ ID NO:11) of a native sequencePRO230 cDNA, wherein SEQ ID NO:11 is a clone designated herein as“DNA33223-1136”.

FIG. 6 shows the amino acid sequence (SEQ ID NO:12) derived from thecoding sequence of SEQ ID NO:11 shown in FIG. 5.

FIG. 7 shows a nucleotide sequence designated herein as DNA20088 (SEQ IDNO:13).

FIG. 8 shows a nucleotide sequence (SEQ ID NO:17) of a native sequencePRO232 cDNA, wherein SEQ ID NO:17 is a clone designated herein as“DNA34435-1140”.

FIG. 9 shows the amino acid sequence (SEQ ID NO:18) derived from thecoding sequence of SEQ ID NO:17 shown in FIG. 8.

FIG. 10 shows a nucleotide sequence (SEQ ID NO:22) of a native sequencePRO187 cDNA, wherein SEQ ID NO:22 is a clone designated herein as“DNA27864-1155”.

FIG. 11 shows the amino acid sequence (SEQ ID NO:23) derived from thecoding sequence of SEQ ID NO:22 shown in FIG. 10.

FIG. 12 shows a nucleotide sequence (SEQ ID NO:27) of a native sequencePRO265 cDNA, wherein SEQ ID NO:27 is a clone designated herein as“DNA36350-1158”.

FIG. 13 shows the amino acid sequence (SEQ ID NO:28) derived from thecoding sequence of SEQ ID NO:27 shown in FIG. 12.

FIG. 14 shows a nucleotide sequence (SEQ ID NO:33) of a native sequencePRO219 cDNA, wherein SEQ ID NO:33 is a clone designated herein as“DNA32290-1164”.

FIG. 15 shows the amino acid sequence (SEQ ID NO:34) derived from thecoding sequence of SEQ ID NO:33 shown in FIG. 14.

FIG. 16 shows a nucleotide sequence (SEQ ID NO:38) of a native sequencePRO246 cDNA, wherein SEQ ID NO:38 is a clone designated herein as“DNA35639-1172”.

FIG. 17 shows the amino acid sequence (SEQ ID NO:39) derived from thecoding sequence of SEQ ID NO:38 shown in FIG. 16.

FIG. 18 shows a nucleotide sequence (SEQ ID NO:48) of a native sequencePRO228 cDNA, wherein SEQ ID NO:48 is a clone designated herein as“DNA33092-1202”.

FIG. 19 shows the amino acid sequence (SEQ ID NO:49) derived from thecoding sequence of SEQ ID NO:48 shown in FIG. 18.

FIG. 20 shows a nucleotide sequence designated herein as DNA21951 (SEQID NO:50).

FIG. 21 shows a nucleotide sequence (SEQ ID NO:58) of a native sequencePRO533 cDNA, wherein SEQ ID NO:58 is a clone designated herein as“DNA49435-1219”.

FIG. 22 shows the amino acid sequence (SEQ ID NO:59) derived from thecoding sequence of SEQ ID NO:58 shown in FIG. 21.

FIG. 23 shows a nucleotide sequence (SEQ ID NO:63) of a native sequencePRO245 cDNA, wherein SEQ ID NO:63 is a clone designated herein as“DNA35638-1141”.

FIG. 24 shows the amino acid sequence (SEQ ID NO:64) derived from thecoding sequence of SEQ ID NO:63 shown in FIG. 23.

FIG. 25 shows a nucleotide sequence (SEQ ID NO:68) of a native sequencePRO220 cDNA, wherein SEQ ID NO:68 is a clone designated herein as“DNA32298-1132”.

FIG. 26 shows the amino acid sequence (SEQ ID NO:69) derived from thecoding sequence of SEQ ID NO:68 shown in FIG. 25.

FIG. 27 shows a nucleotide sequence (SEQ ID NO:70) of a native sequencePRO221 cDNA, wherein SEQ ID NO:70 is a clone designated herein as“DNA33089-1132”.

FIG. 28 shows the amino acid sequence (SEQ ID NO:71) derived from thecoding sequence of SEQ ID NO:70 shown in FIG. 27.

FIG. 29 shows a nucleotide sequence (SEQ ID NO:72) of a native sequencePRO227 cDNA, wherein SEQ ID NO:72 is a clone designated herein as“DNA33786-1132”.

FIG. 30 shows the amino acid sequence (SEQ ID NO:73) derived from thecoding sequence of SEQ ID NO:72 shown in FIG. 29.

FIG. 31 shows a nucleotide sequence (SEQ ID NO:83) of a native sequencePRO258 cDNA, wherein SEQ ID NO:83 is a clone designated herein as“DNA35918-1174”.

FIG. 32 shows the amino acid sequence (SEQ ID NO:84) derived from thecoding sequence of SEQ ID NO:83 shown in FIG. 31.

FIG. 33 shows a nucleotide sequence (SEQ ID NO:90) of a native sequencePRO266 cDNA, wherein SEQ ID NO:90 is a clone designated herein as“DNA37150-1178”.

FIG. 34 shows the amino acid sequence (SEQ ID NO:91) derived from thecoding sequence of SEQ ID NO:90 shown in FIG. 33.

FIG. 35 shows a nucleotide sequence (SEQ ID NO:95) of a native sequencePRO269 cDNA, wherein SEQ ID NO:95 is a clone designated herein as“DNA38260-1180”.

FIG. 36 shows the amino acid sequence (SEQ ID NO:96) derived from thecoding sequence of SEQ ID NO:95 shown in FIG. 35.

FIG. 37 shows a nucleotide sequence (SEQ ID NO:103) of a native sequencePRO287 cDNA, wherein SEQ ID NO:103 is a clone designated herein as“DNA39969-1185”.

FIG. 38 shows the amino acid sequence (SEQ ID NO:104) derived from thecoding sequence of SEQ ID NO:103 shown in FIG. 37.

FIG. 39 shows a nucleotide sequence (SEQ ID NO:108) of a native sequencePRO214 cDNA, wherein SEQ ID NO:108 is a clone designated herein as“DNA32286-1191”.

FIG. 40 shows the amino acid sequence (SEQ ID NO:109) derived from thecoding sequence of SEQ ID NO:108 shown in FIG. 39.

FIG. 41 shows a nucleotide sequence (SEQ ID NO:113) of a native sequencePRO317 cDNA, wherein SEQ ID NO:113 is a clone designated herein as“DNA33461-1199”.

FIG. 42 shows the amino acid sequence (SEQ ID NO:114) derived from thecoding sequence of SEQ ID NO:113 shown in FIG. 41.

FIG. 43 shows a nucleotide sequence (SEQ ID NO:118) of a native sequencePRO301 cDNA, wherein SEQ ID NO:118 is a clone designated herein as“DNA40628-1216”.

FIG. 44 shows the amino acid sequence (SEQ ID NO:119) derived from thecoding sequence of SEQ ID NO:118 shown in FIG. 43.

FIG. 45 shows a nucleotide sequence (SEQ ID NO:126) of a native sequencePRO224 cDNA, wherein SEQ ID NO:126 is a clone designated herein as“DNA33221-1133”.

FIG. 46 shows the amino acid sequence (SEQ ID NO:127) derived from thecoding sequence of SEQ ID NO:126 shown in FIG. 45.

FIG. 47 shows a nucleotide sequence (SEQ ID NO:131) of a native sequencePRO222 cDNA, wherein SEQ ID NO:131 is a clone designated herein as“DNA33107-1135”.

FIG. 48 shows the amino acid sequence (SEQ ID NO:132) derived from thecoding sequence of SEQ ID NO:131 shown in FIG. 47.

FIG. 49 shows a nucleotide sequence (SEQ ID NO:136) of a native sequencePRO234 cDNA, wherein SEQ ID NO:136 is a clone designated herein as“DNA35557-1137”.

FIG. 50 shows the amino acid sequence (SEQ ID NO:137) derived from thecoding sequence of SEQ ID NO:136 shown in FIG. 49.

FIG. 51 shows a nucleotide sequence (SEQ ID NO:141) of a native sequencePRO231 cDNA, wherein SEQ ID NO:141 is a clone designated herein as“DNA34434-1139”.

FIG. 52 shows the amino acid sequence (SEQ ID NO:142) derived from thecoding sequence of SEQ ID NO:141 shown in FIG. 51.

FIG. 53 shows a nucleotide sequence (SEQ ID NO:147) of a native sequencePRO229 cDNA, wherein SEQ ID NO:147 is a clone designated herein as“DNA33100-1159”.

FIG. 54 shows the amino acid sequence (SEQ ID NO:148) derived from thecoding sequence of SEQ ID NO:147 shown in FIG. 53.

FIG. 55 shows a nucleotide sequence (SEQ ID NO:152) of a native sequencePRO238 cDNA, wherein SEQ ID NO:152 is a clone designated herein as“DNA35600-1162”.

FIG. 56 shows the amino acid sequence (SEQ ID NO:153) derived from thecoding sequence of SEQ ID NO:152 shown in FIG. 55.

FIG. 57 shows a nucleotide sequence (SEQ ID NO:158) of a native sequencePRO233 cDNA, wherein SEQ ID NO:158 is a clone designated herein as“DNA34436-1238”.

FIG. 58 shows the amino acid sequence (SEQ ID NO:159) derived from thecoding sequence of SEQ ID NO:158 shown in FIG. 57.

FIG. 59 shows a nucleotide sequence (SEQ ID NO:163) of a native sequencePRO223 cDNA, wherein SEQ ID NO:163 is a clone designated herein as“DNA33206-1165”.

FIG. 60 shows the amino acid sequence (SEQ ID NO:164) derived from thecoding sequence of SEQ ID NO:163 shown in FIG. 59.

FIG. 61 shows a nucleotide sequence (SEQ ID NO:169) of a native sequencePRO235 cDNA, wherein SEQ ID NO:169 is a clone designated herein as“DNA35558-1167”.

FIG. 62 shows the amino acid sequence (SEQ ID NO:170) derived from thecoding sequence of SEQ ID NO:169 shown in FIG. 61.

FIG. 63 shows a nucleotide sequence (SEQ ID NO:174) of a native sequencePRO236 cDNA, wherein SEQ ID NO:174 is a clone designated herein as“DNA35599-1168”.

FIG. 64 shows the amino acid sequence (SEQ ID NO:175) derived from thecoding sequence of SEQ ID NO:174 shown in FIG. 63.

FIG. 65 shows a nucleotide sequence (SEQ ID NO:176) of a native sequencePRO262 cDNA, wherein SEQ ID NO:176 is a clone designated herein as“DNA36992-1168”.

FIG. 66 shows the amino acid sequence (SEQ ID NO:177) derived from thecoding sequence of SEQ ID NO:176 shown in FIG. 65.

FIG. 67 shows a nucleotide sequence (SEQ ID NO:184) of a native sequencePRO239 cDNA, wherein SEQ ID NO:184 is a clone designated herein as“DNA34407-1169”.

FIG. 68 shows the amino acid sequence (SEQ ID NO:185) derived from thecoding sequence of SEQ ID NO:184 shown in FIG. 67.

FIG. 69 shows a nucleotide sequence (SEQ ID NO:189) of a native sequencePRO257 cDNA, wherein SEQ ID NO:189 is a clone designated herein as“DNA35841-1173”.

FIG. 70 shows the amino acid sequence (SEQ ID NO:190) derived from thecoding sequence of SEQ ID NO:189 shown in FIG. 69.

FIG. 71 shows a nucleotide sequence (SEQ ID NO:194) of a native sequencePRO260 cDNA, wherein SEQ ID NO:194 is a clone designated herein as“DNA33470-1175”.

FIG. 72 shows the amino acid sequence (SEQ ID NO:195) derived from thecoding sequence of SEQ ID NO:194 shown in FIG. 71.

FIG. 73 shows a nucleotide sequence (SEQ ID NO:200) of a native sequencePRO263 cDNA, wherein SEQ ID NO:200 is a clone designated herein as“DNA34431-1177”.

FIG. 74 shows the amino acid sequence (SEQ ID NO:201) derived from thecoding sequence of SEQ ID NO:200 shown in FIG. 73.

FIG. 75 shows a nucleotide sequence (SEQ ID NO:206) of a native sequencePRO270 cDNA, wherein SEQ ID NO:206 is a clone designated herein as“DNA39510-1181”.

FIG. 76 shows the amino acid sequence (SEQ ID NO:207) derived from thecoding sequence of SEQ ID NO:206 shown in FIG. 75.

FIG. 77 shows a nucleotide sequence (SEQ ID NO:212) of a native sequencePRO271 cDNA, wherein SEQ ID NO:212 is a clone designated herein as“DNA39423-1182”.

FIG. 78 shows the amino acid sequence (SEQ ID NO:213) derived from thecoding sequence of SEQ ID NO:212 shown in FIG. 77.

FIG. 79 shows a nucleotide sequence (SEQ ID NO:220) of a native sequencePRO272 cDNA, wherein SEQ ID NO:220 is a clone designated herein as“DNA40620-1183”.

FIG. 80 shows the amino acid sequence (SEQ ID NO:221) derived from thecoding sequence of SEQ ID NO:220 shown in FIG. 79.

FIG. 81 shows a nucleotide sequence (SEQ ID NO:226) of a native sequencePRO294 cDNA, wherein SEQ ID NO:226 is a clone designated herein as“DNA40604-1187”.

FIG. 82 shows the amino acid sequence (SEQ ID NO:227) derived from thecoding sequence of SEQ ID NO:226 shown in FIG. 81.

FIG. 83 shows a nucleotide sequence (SEQ ID NO:235) of a native sequencePRO295 cDNA, wherein SEQ ID NO:235 is a clone designated herein as“DNA38268-1188”.

FIG. 84 shows the amino acid sequence (SEQ ID NO:236) derived from thecoding sequence of SEQ ID NO:235 shown in FIG. 83.

FIG. 85 shows a nucleotide sequence (SEQ ID NO:244) of a native sequencePRO293 cDNA, wherein SEQ ID NO:244 is a clone designated herein as“DNA37151-1193”.

FIG. 86 shows the amino acid sequence (SEQ ID NO:245) derived from thecoding sequence of SEQ ID NO:244 shown in FIG. 85.

FIG. 87 shows a nucleotide sequence (SEQ ID NO:249) of a native sequencePRO247 cDNA, wherein SEQ ID NO:249 is a clone designated herein as“DNA35673-1201”.

FIG. 88 shows the amino acid sequence (SEQ ID NO:250) derived from thecoding sequence of SEQ ID NO:249 shown in FIG. 87.

FIG. 89 shows a nucleotide sequence (SEQ ID NO:254) of a native sequencePRO302 cDNA, wherein SEQ ID NO:254 is a clone designated herein as“DNA40370-1217”.

FIG. 90 shows the amino acid sequence (SEQ ID NO:255) derived from thecoding sequence of SEQ ID NO:254 shown in FIG. 89.

FIG. 91 shows a nucleotide sequence (SEQ ID NO:256) of a native sequencePRO303 cDNA, wherein SEQ ID NO:256 is a clone designated herein as“DNA42551-1217”.

FIG. 92 shows the amino acid sequence (SEQ ID NO:257) derived from thecoding sequence of SEQ ID NO:256 shown in FIG. 91.

FIG. 93 shows a nucleotide sequence (SEQ ID NO:258) of a native sequencePRO304 cDNA, wherein SEQ ID NO:258 is a clone designated herein as“DNA39520-1217”.

FIG. 94 shows the amino acid sequence (SEQ ID NO:259) derived from thecoding sequence of SEQ ID NO:258 shown in FIG. 93.

FIG. 95 shows a nucleotide sequence (SEQ ID NO:260) of a native sequencePRO307 cDNA, wherein SEQ ID NO:260 is a clone designated herein as“DNA41225-1217”.

FIG. 96 shows the amino acid sequence (SEQ ID NO:261) derived from thecoding sequence of SEQ ID NO:260 shown in FIG. 95.

FIG. 97 shows a nucleotide sequence (SEQ ID NO:262) of a native sequencePRO343 cDNA, wherein SEQ ID NO:262 is a clone designated herein as“DNA43318-1217”.

FIG. 98 shows the amino acid sequence (SEQ ID NO:263) derived from thecoding sequence of SEQ ID NO:262 shown in FIG. 97.

FIG. 99 shows a nucleotide sequence (SEQ ID NO:284) of a native sequencePRO328 cDNA, wherein SEQ ID NO:284 is a clone designated herein as“DNA40587-1231”.

FIG. 100 shows the amino acid sequence (SEQ ID NO:285) derived from thecoding sequence of SEQ ID NO:284 shown in FIG. 99.

FIG. 101 shows a nucleotide sequence (SEQ ID NO:289) of a nativesequence PRO335 cDNA, wherein SEQ ID NO:289 is a clone designated hereinas “DNA41388-1234”.

FIG. 102 shows the amino acid sequence (SEQ ID NO:290) derived from thecoding sequence of SEQ ID NO:289 shown in FIG. 101.

FIG. 103 shows a nucleotide sequence (SEQ ID NO:291) of a nativesequence PRO331 cDNA, wherein SEQ ID NO:291 is a clone designated hereinas “DNA40981-1234”.

FIG. 104 shows the amino acid sequence (SEQ ID NO:292) derived from thecoding sequence of SEQ ID NO:291 shown in FIG. 103.

FIG. 105 shows a nucleotide sequence (SEQ ID NO:293) of a nativesequence PRO326 cDNA, wherein SEQ ID NO:293 is a clone designated hereinas “DNA37140-1234”.

FIG. 106 shows the amino acid sequence (SEQ ID NO:294) derived from thecoding sequence of SEQ ID NO:293 shown in FIG. 105.

FIG. 107 shows a nucleotide sequence (SEQ ID NO:309) of a nativesequence PRO332 cDNA, wherein SEQ ID NO:309 is a clone designated hereinas “DNA40982-1235”.

FIG. 108 shows the amino acid sequence (SEQ ID NO:310) derived from thecoding sequence of SEQ ID NO:309 shown in FIG. 107.

FIG. 109 shows a nucleotide sequence (SEQ ID NO:314) of a nativesequence PRO334 cDNA, wherein SEQ ID NO:314 is a clone designated hereinas “DNA41379-1236”.

FIG. 110 shows the amino acid sequence (SEQ ID NO:315) derived from thecoding sequence of SEQ ID NO:314 shown in FIG. 109.

FIG. 111 shows a nucleotide sequence (SEQ ID NO:319) of a nativesequence PRO346 cDNA, wherein SEQ ID NO:319 is a clone designated hereinas “DNA44167-1243”.

FIG. 112 shows the amino acid sequence (SEQ ID NO:320) derived from thecoding sequence of SEQ ID NO:319 shown in FIG. 111.

FIG. 113 shows a nucleotide sequence (SEQ ID NO:324) of a nativesequence PRO268 cDNA, wherein SEQ ID NO:324 is a clone designated hereinas “DNA39427-1179”.

FIG. 114 shows the amino acid sequence (SEQ ID NO:325) derived from thecoding sequence of SEQ ID NO:324 shown in FIG. 113.

FIG. 115 shows a nucleotide sequence (SEQ ID NO:331) of a nativesequence PRO330 cDNA, wherein SEQ ID NO:331 is a clone designated hereinas “DNA40603-1232”.

FIG. 116 shows the amino acid sequence (SEQ ID NO:332) derived from thecoding sequence of SEQ ID NO:331 shown in FIG. 115.

FIG. 117 shows a nucleotide sequence (SEQ ID NO:338) of a nativesequence PRO339 cDNA, wherein SEQ ID NO:338 is a clone designated hereinas “DNA43466-1225”.

FIG. 118 shows the amino acid sequence (SEQ ID NO:339) derived from thecoding sequence of SEQ ID NO:338 shown in FIG. 117.

FIG. 119 shows a nucleotide sequence (SEQ ID NO:340) of a nativesequence PRO310 cDNA, wherein SEQ ID NO:340 is a clone designated hereinas “DNA43046-1225”.

FIG. 120 shows the amino acid sequence (SEQ ID NO:341) derived from thecoding sequence of SEQ ID NO:340 shown in FIG. 119.

FIG. 121 shows a nucleotide sequence (SEQ ID NO:376) of a nativesequence PRO244 cDNA, wherein SEQ ID NO:376 is a clone designated hereinas “DNA35668-1171”.

FIG. 122 shows the amino acid sequence (SEQ ID NO:377) derived from thecoding sequence of SEQ ID NO:376 shown in FIG. 121.

FIG. 123 shows a nucleotide sequence (SEQ ID NO:422) of a nativesequence PRO1868 cDNA, wherein SEQ ID NO:422 is a clone designatedherein as “DNA77624-2515”.

FIG. 124 shows the amino acid sequence (SEQ ID NO:423) derived from thecoding sequence of SEQ ID NO:422 shown in FIG. 123.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

I. Definitions

The terms “PRO polypeptide” and “PRO” as used herein and whenimmediately followed by a numerical designation refer to variouspolypeptides, wherein the complete designation (i.e., PRO/number) refersto specific polypeptide sequences as described herein. The terms“PRO/number polypeptide” and “PRO/number” wherein the term “number” isprovided as an actual numerical designation as used herein encompassnative sequence polypeptides and polypeptide variants (which are furtherdefined herein). The PRO polypeptides described herein may be isolatedfrom a variety of sources, such as from human tissue types or fromanother source, or prepared by recombinant or synthetic methods.

A “native sequence PRO polypeptide” comprises a polypeptide having thesame amino acid sequence as the corresponding PRO polypeptide derivedfrom nature. Such native sequence PRO polypeptides can be isolated fromnature or can be produced by recombinant or synthetic means. The term“native sequence PRO polypeptide” specifically encompassesnaturally-occurring truncated or secreted forms of the specific PROpolypeptide (e.g., an extracellular domain sequence),naturally-occurring variant forms (e.g., alternatively spliced forms)and naturally-occurring allelic variants of the polypeptide. In variousembodiments of the invention, the native sequence PRO polypeptidesdisclosed herein are mature or full-length native sequence polypeptidescomprising the full-length amino acids sequences shown in theaccompanying figures. Start and stop codons are shown in bold font andunderlined in the figures. However, while the PRO polypeptide disclosedin the accompanying figures are shown to begin with methionine residuesdesignated herein as amino acid position 1 in the figures, it isconceivable and possible that other methionine residues located eitherupstream or downstream from the amino acid position 1 in the figures maybe employed as the starting amino acid residue for the PRO polypeptides.

The PRO polypeptide “extracellular domain” or “ECD” refers to a form ofthe PRO polypeptide which is essentially free of the transmembrane andcytoplasmic domains. Ordinarily, a PRO polypeptide ECD will have lessthan 1% of such transmembrane and/or cytoplasmic domains and preferably,will have less than 0.5% of such domains. It will be understood that anytransmembrane domains identified for the PRO polypeptides of the presentinvention are identified pursuant to criteria routinely employed in theart for identifying that type of hydrophobic domain. The exactboundaries of a transmembrane domain may vary but most likely by no morethan about 5 amino acids at either end of the domain as initiallyidentified herein. Optionally, therefore, an extracellular domain of aPRO polypeptide may contain from about 5 or fewer amino acids on eitherside of the transmembrane domain/extracellular domain boundary asidentified in the Examples or specification and such polypeptides, withor without the associated signal peptide, and nucleic acid encodingthem, are contemplated by the present invention.

The approximate location of the “signal peptides” of the various PROpolypeptides disclosed herein are shown in the present specificationand/or the accompanying figures. It is noted, however, that theC-terminal boundary of a signal peptide may vary, but most likely by nomore than about 5 amino acids on either side of the signal peptideC-terminal boundary as initially identified herein, wherein theC-terminal boundary of the signal peptide may be identified pursuant tocriteria routinely employed in the art for identifying that type ofamino acid sequence element (e.g., Nielsen et al., Prot. Eng.10:1-6(1997) and von Heinje et al., Nucl. Acids. Res. 14:4683-4690(1986)). Moreover, it is also recognized that, in some cases, cleavageof a signal sequence from a secreted polypeptide is not entirelyuniform, resulting in more than one secreted species. These maturepolypeptides, where the signal peptide is cleaved within no more thanabout 5 amino acids on either side of the C-terminal boundary of thesignal peptide as identified herein, and the polynucleotides encodingthem, are contemplated by the present invention.

“PRO polypeptide variant” means an active PRO polypeptide as definedabove or below having at least about 80% amino acid sequence identitywith a full-length native sequence PRO polypeptide sequence as disclosedherein, a PRO polypeptide sequence lacking the signal peptide asdisclosed herein, an extracellular domain of a PRO polypeptide, with orwithout the signal peptide, as disclosed herein or any other fragment ofa full-length PRO polypeptide sequence as disclosed herein. Such PROpolypeptide variants include, for instance, PRO polypeptides wherein oneor more amino acid residues are added, or deleted, at the N- orC-terminus of the full-length native amino acid sequence. Ordinarily, aPRO polypeptide variant will have at least about 80% amino acid sequenceidentity, preferably at least about 81% amino acid sequence identity,more preferably at least about 82% amino acid sequence identity, morepreferably at least about 83% amino acid sequence identity, morepreferably at least about 84% amino acid sequence identity, morepreferably at least about 85% amino acid sequence identity, morepreferably at least about 86% amino acid sequence identity, morepreferably at least about 87% amino acid sequence identity, morepreferably at least about 88% amino acid sequence identity, morepreferably at least about 89% amino acid sequence identity, morepreferably at least about 90% amino acid sequence identity, morepreferably at least about 91% amino acid sequence identity, morepreferably at least about 92% amino acid sequence identity, morepreferably at least about 93% amino acid sequence identity, morepreferably at least about 94% amino acid sequence identity, morepreferably at least about 95% amino acid sequence identity, morepreferably at least about 96% amino acid sequence identity, morepreferably at least about 97% amino acid sequence identity, morepreferably at least about 98% amino acid sequence identity and mostpreferably at least about 99% amino acid sequence identity with afull-length native sequence PRO polypeptide sequence as disclosedherein, a PRO polypeptide sequence lacking the signal peptide asdisclosed herein, an extracellular domain of a PRO polypeptide, with orwithout the signal peptide, as disclosed herein or any otherspecifically defined fragment of a full-length PRO polypeptide sequenceas disclosed herein. Ordinarily, PRO variant polypeptides are at leastabout 10 amino acids in length, often at least about 20 amino acids inlength, more often at least about 30 amino acids in length, more oftenat least about 40 amino acids in length, more often at least about 50amino acids in length, more often at least about 60 amino acids inlength, more often at least about 70 amino acids in length, more oftenat least about 80 amino acids in length, more often at least about 90amino acids in length, more often at least about 100 amino acids inlength, more often at least about 150 amino acids in length, more oftenat least about 200 amino acids in length, more often at least about 300amino acids in length, or more.

“Percent (%) amino acid sequence identity” with respect to the PROpolypeptide sequences identified herein is defined as the percentage ofamino acid residues in a candidate sequence that are identical with theamino acid residues in the specific PRO polypeptide sequence, afteraligning the sequences and introducing gaps, if necessary, to achievethe maximum percent sequence id entity, and not considering anyconservative substitutions as part of the sequence identity. Alignmentfor purposes of determining percent amino acid sequence identity can beachieved in various ways that are within the skill in the art, forinstance, using publicly available computer software such as BLAST,BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the artcan determine appropriate parameters for measuring alignment, includingany algorithms needed to achieve maximal alignment over the full lengthof the sequences being compared. For purposes herein, however, % aminoacid sequence identity values are generated using the sequencecomparison computer program ALIGN-2, wherein the complete source codefor the ALIGN-2 program is provided in Table 1 below. The ALIGN-2sequence comparison computer program was authored by Genentech, Inc. andthe source code shown in Table 1 below has been filed with userdocumentation in the U.S. Copyright Office, Washington D.C., 20559,where it is registered under U.S. Copyright Registration No. TXU510087.The ALIGN-2 program is publicly available through Genentech, Inc., SouthSan Francisco, Calif. or may be compiled from the source code providedin Table 1 below. The ALIGN-2 program should be compiled for use on aUNIX operating system, preferably digital UNIX V4.0D. All sequencecomparison parameters are set by the ALIGN-2 program and do not vary.

In situations where ALIGN-2 is employed for amino acid sequencecomparisons, the % amino acid sequence identity of a given amino acidsequence A to, with, or against a given amino acid sequence B (which canalternatively be phrased as a given amino acid sequence A that has orcomprises a certain % amino acid sequence identity to, with, or againsta given amino acid sequence B) is calculated as follows:

100 times the fraction X/Y

where X is the number of amino acid residues scored as identical matchesby the sequence alignment program ALIGN-2 in that program's alignment ofA and B, and where Y is the total number of amino acid residues in B. Itwill be appreciated that where the length of amino acid sequence A isnot equal to the length of amino acid sequence B, the % amino acidsequence identity of A to B will not equal the % amino acid sequenceidentity of B to A. As examples of % amino acid sequence identitycalculations using this method, Tables 2 and 3 demonstrate how tocalculate the % amino acid sequence identity of the amino acid sequencedesignated “Comparison Protein” to the amino acid sequence designated“PRO”, wherein “PRO” represents the amino acid sequence of ahypothetical PRO polypeptide of interest, “Comparison Protein”represents the amino acid sequence of a polypeptide against which the“PRO” polypeptide of interest is being compared, and “X, “Y” and “Z”each represent different hypothetical amino acid residues.

Unless specifically stated otherwise, all % amino acid sequence identityvalues used herein are obtained as described in the immediatelypreceding paragraph using the ALIGN-2 computer program. However, % aminoacid sequence identity values may also be obtained as described below byusing the WU-BLAST-2 computer program (Altschul et al., Methods inEnzymology 266:460-480 (1996)). Most of the WU-BLAST-2 search parametersare set to the default values. Those not set to default values, i.e.,the adjustable parameters, are set with the following values: overlapspan=1, overlap fraction=0.125, word threshold (T)=11, and scoringmatrix=BLOSUM62. When WU-BLAST-2 is employed, a % amino acid sequenceidentity value is determined by dividing (a) the number of matchingidentical amino acid residues between the amino acid sequence of the PROpolypeptide of interest having a sequence derived from the native PROpolypeptide and the comparison amino acid sequence of interest (i.e.,the sequence against which the PRO polypeptide of interest is beingcompared which may be a PRO variant polypeptide) as determined byWU-BLAST-2 by (b) the total number of amino acid residues of the PROpolypeptide of interest. For example, in the statement “a polypeptidecomprising an the amino acid sequence A which has or having at least 80%amino acid sequence identity to the amino acid sequence B”, the aminoacid sequence A is the comparison amino acid sequence of interest andthe amino acid sequence B is the amino acid sequence of the PROpolypeptide of interest.

Percent amino acid sequence identity may also be determined using thesequence comparison program NCBI-BLAST2 (Altschul et al., Nucleic AcidsRes. 25:3389-3402 (1997)). NCBI-BLAST2 uses several search parameters,wherein all of those search parameters are set to default valuesincluding, for example, unmask=yes, strand=all, expected occurrences=10,minimum low complexity length=15/5, multi-pass e-value=0.01, constantfor multi-pass=25, dropoff for final gapped alignment=25 and scoringmatrix=BLOSUM62.

In situations where NCBI-BLAST2 is employed for amino acid sequencecomparisons, the % amino acid sequence identity of a given amino acidsequence A to, with, or against a given amino acid sequence B (which canalternatively be phrased as a given amino acid sequence A that has orcomprises a certain % amino acid sequence identity to, with, or againsta given amino acid sequence B) is calculated as follows:

100 times the fraction X/Y

where X is the number of amino acid residues scored as identical matchesby the sequence alignment program NCBI-BLAST2 in that program'salignment of A and B, and where Y is the total number of amino acidresidues in B. It will be appreciated that where the length of aminoacid sequence A is not equal to the length of amino acid sequence B, the% amino acid sequence identity of A to B will not equal the % amino acidsequence identity of B to A.

“PRO variant polynucleotide” or “PRO variant nucleic acid sequence”means a nucleic acid molecule which encodes an active PRO polypeptide asdefined below and which has at least about 80% nucleic acid sequenceidentity with a nucleotide acid sequence encoding a full-length nativesequence PRO polypeptide sequence as disclosed herein, a full-lengthnative sequence PRO polypeptide sequence lacking the signal peptide asdisclosed herein, an extracellular domain of a PRO polypeptide, with orwithout the signal peptide, as disclosed herein or any other fragment ofa full-length PRO polypeptide sequence as disclosed herein. Ordinarily,a PRO variant polynucleotide will have at least about 80% nucleic acidsequence identity, more preferably at least about 81% nucleic acidsequence identity, more preferably at least about 82% nucleic acidsequence identity, more preferably at least about 83% nucleic acidsequence identity, more preferably at least about 84% nucleic acidsequence identity, more preferably at least about 85% nucleic acidsequence identity, more preferably at least about 86% nucleic acidsequence identity, more preferably at least about 87% nucleic acidsequence identity, more preferably at least about 88% nucleic acidsequence identity, more preferably at least about 89% nucleic acidsequence identity, more preferably at least about 90% nucleic acidsequence identity, more preferably at least about 91% nucleic acidsequence identity, more preferably at least about 92% nucleic acidsequence identity, more preferably at least about 93% nucleic acidsequence identity, more preferably at least about 94% nucleic acidsequence identity, more preferably at least about 95% nucleic acidsequence identity, more preferably at least about 96% nucleic acidsequence identity, more preferably at least about 97% nucleic acidsequence identity, more preferably at least about 98% nucleic acidsequence identity and yet more preferably at least about 99% nucleicacid sequence identity with a nucleic acid sequence encoding afull-length native sequence PRO polypeptide sequence as disclosedherein, a full-length native sequence PRO polypeptide sequence lackingthe signal peptide as disclosed herein, an extracellular domain of a PROpolypeptide, with or without the signal sequence, as disclosed herein orany other fragment of a full-length PRO polypeptide sequence asdisclosed herein. Variants do not encompass the native nucleotidesequence.

Ordinarily, PRO variant polynucleotides are at least about 30nucleotides in length, often at least about 60 nucleotides in length,more often at least about 90 nucleotides in length, more often at leastabout 120 nucleotides in length, more often at least about 150nucleotides in length, more often at least about 180 nucleotides inlength, more often at least about 210 nucleotides in length, more oftenat least about 240 nucleotides in length, more often at least about 270nucleotides in length, more often at least about 300 nucleotides inlength, more often at least about 450 nucleotides in length, more oftenat least about 600 nucleotides in length, more often at least about 900nucleotides in length, or more.

“Percent (%) nucleic acid sequence identity” with respect toPRO-encoding nucleic acid sequences identified herein is defined as thepercentage of nucleotides in a candidate sequence that are identicalwith the nucleotides in the PRO nucleic acid sequence of interest, afteraligning the sequences and introducing gaps, if necessary, to achievethe maximum percent sequence identity. Alignment for purposes ofdetermining percent nucleic acid sequence identity can be achieved invarious ways that are within the skill in the art, for instance, usingpublicly available computer software such as BLAST, BLAST-2, ALIGN orMegalign (DNASTAR) software. For purposes herein, however, % nucleicacid sequence identity values are generated using the sequencecomparison computer program ALIGN-2, wherein the complete source codefor the ALIGN-2 program is provided in Table 1 below. The ALIGN-2sequence comparison computer program was authored by Genentech, Inc. andthe source code shown in Table 1 below has been filed with userdocumentation in the U.S. Copyright Office, Washington D.C., 20559,where it is registered under U.S. Copyright Registration No. TXU510087.The ALIGN-2 program is publicly available through Genentech, Inc., SouthSan Francisco, Calif. or may be compiled from the source code providedin Table 1 below. The ALIGN-2 program should be compiled for use on aUNIX operating system, preferably digital UNIX V4.0D. All sequencecomparison parameters are set by the ALIGN-2 program and do not vary.

In situations where ALIGN-2 is employed for nucleic acid sequencecomparisons, the % nucleic acid sequence identity of a given nucleicacid sequence C to, with, or against a given nucleic acid sequence D(which can alternatively be phrased as a given nucleic acid sequence Cthat has or comprises a certain % nucleic acid sequence identity to,with, or against a given nucleic acid sequence D) is calculated asfollows:

100 times the fraction W/Z

where W is the number of nucleotides scored as identical matches by thesequence alignment program ALIGN-2 in that program's alignment of C andD, and where Z is the total number of nucleotides in D. It will beappreciated that where the length of nucleic acid sequence C is notequal to the length of nucleic acid sequence D, the % nucleic acidsequence identity of C to D will not equal the % nucleic acid sequenceidentity of D to C. As examples of % nucleic acid sequence identitycalculations, Tables 4 and 5, demonstrate how to calculate the % nucleicacid sequence identity of the nucleic acid sequence designated“Comparison DNA” to the nucleic acid sequence designated “PRO-DNA”,wherein “PRO-DNA” represents a hypothetical PRO-encoding nucleic acidsequence of interest, “Comparison DNA” represents the nucleotidesequence of a nucleic acid molecule against which the “PRO-DNA” nucleicacid molecule of interest is being compared, and “N”, “L” and “V” eachrepresent different hypothetical nucleotides.

Unless specifically stated otherwise, all % nucleic acid sequenceidentity values used herein are obtained as described in the immediatelypreceding paragraph using the ALIGN-2 computer program. However, %nucleic acid sequence identity values may also be obtained as describedbelow by using the WU-BLAST-2 computer program (Altschul et al., Methodsin Enzymology 266:460-480 (1996)). Most of the WU-BLAST-2 searchparameters are set to the default values. Those not set to defaultvalues, i.e., the adjustable parameters, are set with the followingvalues: overlap span=1, overlap fraction=0.125, word threshold (T)=11,and scoring matrix=BLOSUM62. When WU-BLAST-2 is employed, a % nucleicacid sequence identity value is determined by dividing (a) the number ofmatching identical nucleotides between the nucleic acid sequence of thePRO polypeptide-encoding nucleic acid molecule of interest having asequence derived from the native sequence PRO polypeptide-encodingnucleic acid and the comparison nucleic acid molecule of interest (i.e.,the sequence against which the PRO polypeptide-encoding nucleic acidmolecule of interest is being compared which may be a variant PROpolynucleotide) as determined by WU-BLAST-2 by (b) the total number ofnucleotides of the PRO polypeptide-encoding nucleic acid molecule ofinterest. For example, in the statement “an isolated nucleic acidmolecule comprising a nucleic acid sequence A which has or having atleast 80% nucleic acid sequence identity to the nucleic acid sequenceB”, the nucleic acid sequence A is the comparison nucleic acid moleculeof interest and the nucleic acid sequence B is the nucleic acid sequenceof the PRO polypeptide-encoding nucleic acid molecule of interest.

Percent nucleic acid sequence identity may also be determined using thesequence comparison program, NCBI-BLAST2 (Altschul et al., Nucleic AcidsRes. 25:3389-3402 (1997)). NCBI-BLAST2 uses several search parameters,wherein all of those search parameters are set to default valuesincluding, for example, unmask=yes, strand=all, expected occurrences=10,minimum low complexity length=15/5, multi-pass e-value=0.01, constantfor multi-pass=25, dropoff for final gapped alignment=25 and scoringmatrix=BLOSUM62.

In situations where NCBI-BLAST2 is employed for sequence comparisons,the % nucleic acid sequence identity of a given nucleic acid sequence Cto, with, or against a given nucleic acid sequence D (which canalternatively be phrased as a given nucleic acid sequence C that has orcomprises a certain % nucleic acid sequence identity to, with, oragainst a given nucleic acid sequence D) is calculated as follows:

100 times the fraction W/Z

where W is the number of nucleotides scored as identical matches by thesequence alignment program NCBI-BLAST2 in that program's alignment of Cand D, and where Z is the total number of nucleotides in D. It will beappreciated that where the length of nucleic acid sequence C is notequal to the length of nucleic acid sequence D, the % nucleic acidsequence identity of C to D will not equal the % nucleic acid sequenceidentity of D to C.

In other embodiments, PRO variant polynucleotides are nucleic acidmolecules that encode an active PRO polypeptide and which are capable ofhybridizing, preferably under stringent hybridization and washconditions, to nucleotide sequences encoding a full-length PROpolypeptide as disclosed herein. PRO variant polypeptides may be thosethat are encoded by a PRO variant polynucleotide.

The term “positives”, in the context of sequence comparison performed asdescribed above, includes residues in the sequences compared that arenot identical but have similar properties (e.g. as a result ofconservative substitutions, see Table 6 below). For purposes herein, the% value of positives is determined by dividing (a) the number of aminoacid residues scoring a positive value between the PRO polypeptide aminoacid sequence of interest having a sequence derived from the native PROpolypeptide sequence and the comparison amino acid sequence of interest(i.e., the amino acid sequence against which the PRO polypeptidesequence is being compared) as determined in the BLOSUM62 matrix ofWU-BLAST-2 by (b) the total number of amino acid residues of the PROpolypeptide of interest.

Unless specifically stated otherwise, the % value of positives iscalculated as described in the immediately preceding paragraph. However,in the context of the amino acid sequence identity comparisons performedas described for ALIGN-2 and NCBI-BLAST-2 above, includes amino acidresidues in the sequences compared that are not only identical, but alsothose that have similar properties. Amino acid residues that score apositive value to an amino acid residue of interest are those that areeither identical to the amino acid residue of interest or are apreferred substitution (as defined in Table 6 below) of the amino acidresidue of interest.

For amino acid sequence comparisons using ALIGN-2 or NCBI-BLAST2, the %value of positives of a given amino acid sequence A to, with, or againsta given amino acid sequence B (which can alternatively be phrased as agiven amino acid sequence A that has or comprises a certain % positivesto, with, or against a given amino acid sequence B) is calculated asfollows:

100 times the fraction X/Y

where X is the number of amino acid residues scoring a positive value asdefined above by the sequence alignment program ALIGN-2 or NCBI-BLAST2in that program's alignment of A and B, and where Y is the total numberof amino acid residues in B. It will be appreciated that where thelength of amino acid sequence A is not equal to the length of amino acidsequence B, the % positives of A to B will not equal the % positives ofB to A.

“Isolated, ” when used to describe the various polypeptides disclosedherein, means polypeptide that has been identified and separated and/orrecovered from a component of its natural environment. Contaminantcomponents of its natural environment are materials that would typicallyinterfere with diagnostic or therapeutic uses for the polypeptide, andmay include enzymes, hormones, and other proteinaceous ornon-proteinaceous solutes. In preferred embodiments, the polypeptidewill be purified (1) to a degree sufficient to obtain at least 15residues of N-terminal or internal amino acid sequence by use of aspinning cup sequenator, or (2) to homogeneity by SDS-PAGE undernon-reducing or reducing conditions using Coomassie blue or, preferably,silver stain. Isolated polypeptide includes polypeptide in situ withinrecombinant cells, since at least one component of the PRO polypeptidenatural environment will not be present. Ordinarily, however, isolatedpolypeptide will be prepared by at least one purification step.

An “isolated” PRO polypeptide-encoding nucleic acid or otherpolypeptide-encoding nucleic acid is a nucleic acid molecule that isidentified and separated from at least one contaminant nucleic acidmolecule with which it is ordinarily associated in the natural source ofthe polypeptide-encoding nucleic acid. An isolated polypeptide-encodingnucleic acid molecule is other than in the form or setting in which itis found in nature. Isolated polypeptide-encoding nucleic acid moleculestherefore are distinguished from the specific polypeptide-encodingnucleic acid molecule as it exists in natural cells. However, anisolated polypeptide-encoding nucleic acid molecule includespolypeptide-encoding nucleic acid molecules contained in cells thatordinarily express the polypeptide where, for example, the nucleic acidmolecule is in a chromosomal location different from that of naturalcells.

The term “control sequences” refers to DNA sequences necessary for theexpression of an operably linked coding sequence in a particular hostorganism. The control sequences that are suitable for prokaryotes, forexample, include a promoter, optionally an operator sequence, and aribosome binding site. Eukaryotic cells are known to utilize promoters,polyadenylation signals, and enhancers.

Nucleic acid is “operably linked” when it is placed into a functionalrelationship with another nucleic acid sequence. For example, DNA for apresequence or secretory leader is operably linked to DNA for apolypeptide if it is expressed as a preprotein that participates in thesecretion of the polypeptide; a promoter or enhancer is operably linkedto a coding sequence if it affects the transcription of the sequence; ora ribosome binding site is operably linked to a coding sequence if it ispositioned so as to facilitate translation. Generally, “operably linked”means that the DNA sequences being linked are contiguous, and, in thecase of a secretory leader, contiguous and in reading phase. However,enhancers do not have to be contiguous. Linking is accomplished byligation at convenient restriction sites. If such sites do not exist,the synthetic oligonucleotide adaptors or linkers are used in accordancewith conventional practice.

The term “antibody” is used in the broadest sense and specificallycovers, for example, single anti-PRO monoclonal antibodies (includingagonist, antagonist, and neutralizing antibodies), anti-PRO antibodycompositions with polyepitopic specificity, single chain anti-PROantibodies, and fragments of anti-PRO antibodies (see below). The term“monoclonal antibody” as used herein refers to an antibody obtained froma population of substantially homogeneous antibodies, i.e., theindividual antibodies comprising the population are identical except forpossible naturally-occurring mutations that may be present in minoramounts.

“Stringency” of hybridization reactions is readily determinable by oneof ordinary skill in the art, and generally is an empirical calculationdependent upon probe length, washing temperature, and saltconcentration. In general, longer probes require higher temperatures forproper annealing, while shorter probes need lower temperatures.Hybridization generally depends on the ability of denatured DNA toreanneal when complementary strands are present in an environment belowtheir melting temperature. The higher the degree of desired homologybetween the probe and hybridizable sequence, the higher the relativetemperature which can be used. As a result, it follows that higherrelative temperatures would tend to make the reaction conditions morestringent, while lower temperatures less so. For additional details andexplanation of stringency of hybridization reactions, see Ausubel etal., Current Protocols in Molecular Biology, Wiley IntersciencePublishers, (1995).

“Stringent conditions” or “high stringency conditions”, as definedherein, may be identified by those that: (1) employ low ionic strengthand high temperature for washing, for example 0.015 M sodiumchloride/0.0015 M sodium citrate/0.1% sodium dodecyl sulfate at 50° C.;(2) employ during hybridization a denaturing agent, such as formamide,for example, 50% (v/v) formamide with 0.1% bovine serum albumin/0.1%Ficoll/0.1% polyvinylpyrrolidone/50 mM sodium phosphate buffer at pH 6.5with 750 mM sodium chloride, 75 mM sodium citrate at 42° C.; or (3)employ 50% formamide, 5×SSC (0.75 M NaCl, 0.075 M sodium citrate), 50 mMsodium phosphate (pH 6.8), 0.1% sodium pyrophosphate, 5×Denhardt'ssolution, sonicated salmon sperm DNA (50 μg/ml), 0.1% SDS, and 10%dextran sulfate at 42° C., with washes at 42° C. in 0.2×SSC (sodiumchloride/sodium citrate) and 50% formamide at 55° C., followed by ahigh-stringency wash consisting of 0.1×SSC containing EDTA at 55° C.

“Moderately stringent conditions” may be identified as described bySambrook et al., Molecular Cloning: A Laboratory Manual, New York: ColdSpring Harbor Press, 1989, and include the use of washing solution andhybridization conditions (e.g., temperature, ionic strength and % SDS)less stringent that those described above. An example of moderatelystringent conditions is overnight incubation at 37° C. in a solutioncomprising: 20% formamide, 5×SSC (150 mM NaCl, 15 mM trisodium citrate),50 mM sodium phosphate (pH 7.6), 5×Denhardt's solution, 10% dextransulfate, and 20 mg/ml denatured sheared salmon sperm DNA, followed bywashing the filters in 1×SSC at about 37-50° C. The skilled artisan willrecognize how to adjust the temperature, ionic strength, etc. asnecessary to accommodate factors such as probe length and the like.

The term “epitope tagged” when used herein refers to a chimericpolypeptide comprising a PRO polypeptide fused to a “tag polypeptide”.The tag polypeptide has enough residues to provide an epitope againstwhich an antibody can be made, yet is short enough such that it does notinterfere with activity of the polypeptide to which it is fused. The tagpolypeptide preferably also is fairly unique so that the antibody doesnot substantially cross-react with other epitopes. Suitable tagpolypeptides generally have at least six amino acid residues and usuallybetween about 8 and 50 amino acid residues (preferably, between about 10and 20 amino acid residues).

As used herein, the term “immunoadhesin” designates antibody-likemolecules which combine the binding specificity of a heterologousprotein (an “adhesin”) with the effector functions of immunoglobulinconstant domains. Structurally, the immunoadhesin comprise a fusion ofan amino acid sequence with the desired binding specificity which isother than the antigen recognition and binding site of an antibody(i.e., is “heterologous”), and an immunoglobulin constant domainsequence. The adhesin part of an immunoadhesin molecule typically is acontiguous amino acid sequence comprising at least the binding site of areceptor or a ligand. The immunoglobulin constant domain sequence in theimmunoadhesin may be obtained from any immunoglobulin, such as IgG-1,IgG-2, IgG-3, or IgG4 subtypes, IgA (including IgA-1 and IgA-2), IgE,IgD or IgM.

“Active” or “activity” for the purposes herein refers to form(s) of aPRO polypeptide which retain a biological and/or an immunologicalactivity of native or naturally-occurring PRO, wherein “biological”activity refers to a biological function (either inhibitory orstimulatory) caused by a native or naturally-occurring PRO other thanthe ability to induce the production of an antibody against an antigenicepitope possessed by a native or naturally-occurring PRO and an“immunological” activity refers to the ability to induce the productionof an antibody against an antigenic epitope possessed by a native ornaturally-occurring PRO.

The term “antagonist” is used in the broadest sense, and includes anymolecule that partially or fully blocks, inhibits, or neutralizes abiological activity of a native PRO polypeptide disclosed herein. In asimilar manner, the term “agonist” is used in the broadest sense andincludes any molecule that mimics a biological activity of a native PROpolypeptide disclosed herein. Suitable agonist or antagonist moleculesspecifically include agonist or antagonist antibodies or antibodyfragments, fragments or amino acid sequence variants of native PROpolypeptides, peptides, antisense oligonucleotides, small organicmolecules, etc. Methods for identifying agonists or antagonists of a PROpolypeptide may comprise contacting a PRO polypeptide with a candidateagonist or antagonist molecule and measuring a detectable change in oneor more biological activities normally associated with the PROpolypeptide.

“Treatment” refers to both therapeutic treatment and prophylactic orpreventative measures, wherein the object is to prevent or slow down(lessen) the targeted pathologic condition or disorder. Those in need oftreatment include those already with the disorder as well as those proneto have the disorder or those in whom the disorder is to be prevented.

“Chronic” administration refers to administration of the agent(s) in acontinuous mode as opposed to an acute mode, so as to maintain theinitial therapeutic effect (activity) for an extended period of time.“Intermittent” administration is treatment that is not consecutivelydone without interruption, but rather is cyclic in nature.

“Mammal” for purposes of treatment refers to any animal classified as amammal, including humans, domestic and farm animals, and zoo, sports, orpet animals, such as dogs, cats, cattle, horses, sheep, pigs, goats,rabbits, etc. Preferably, the mammal is human.

Administration “in combination with” one or more further therapeuticagents includes simultaneous (concurrent) and consecutive administrationin any order.

“Carriers” as used herein include pharmaceutically acceptable carriers,excipients, or stabilizers which are nontoxic to the cell or mammalbeing exposed thereto at the dosages and concentrations employed. Oftenthe physiologically acceptable carrier is an aqueous pH bufferedsolution. Examples of physiologically acceptable carriers includebuffers such as phosphate, citrate, and other organic acids;antioxidants including ascorbic acid; low molecular weight (less thanabout 10 residues) polypeptide; proteins, such as serum albumin,gelatin, or immunoglobulins; hydrophilic polymers such aspolyvinylpyrrolidone; amino acids such as glycine, glutamine,asparagine, arginine or lysine; monosaccharides, disaccharides, andother carbohydrates including glucose, mannose, or dextrins; chelatingagents such as EDTA; sugar alcohols such as mannitol or sorbitol;salt-forming counterions such as sodium; and/or nonionic surfactantssuch as TWEEN™, polyethylene glycol (PEG), and PLURONICS™.

“Antibody fragments” comprise a portion of an intact antibody,preferably the antigen binding or variable region of the intactantibody. Examples of antibody fragments include Fab, Fab′, F(ab′)₂, andFv fragments; diabodies; linear antibodies (Zapata et al., Protein Eng.8(10): 1057-1062 [1995]); single-chain antibody molecules; andmultispecific antibodies formed from antibody fragments.

Papain digestion of antibodies produces two identical antigen-bindingfragments, called “Fab” fragments, each with a single antigen-bindingsite, and a residual “Fc” fragment, a designation reflecting the abilityto crystallize readily. Pepsin treatment yields an F(ab′)₂ fragment thathas two antigen-combining sites and is still capable of cross-linkingantigen.

“Fv” is the minimum antibody fragment which contains a completeantigen-recognition and -binding site. This region consists of a dimerof one heavy- and one light-chain variable domain in tight, non-covalentassociation. It is in this configuration that the three CDRs of eachvariable domain interact to define an antigen-binding site on thesurface of the V_(H)-V_(L) dimer. Collectively, the six CDRs conferantigen-binding specificity to the antibody. However, even a singlevariable domain (or half of an Fv comprising only three CDRs specificfor an antigen) has the ability to recognize and bind antigen, althoughat a lower affinity than the entire binding site.

The Fab fragment also contains the constant domain of the light chainand the first constant domain (CH1) of the heavy chain. Fab fragmentsdiffer from Fab′ fragments by the addition of a few residues at thecarboxy terminus of the heavy chain CH1 domain including one or morecysteines from the antibody hinge region. Fab′-SH is the designationherein for Fab′ in which the cysteine residue(s) of the constant domainsbear a free thiol group. F(ab′)₂ antibody fragments originally wereproduced as pairs of Fab′ fragments which have hinge cysteines betweenthem. Other chemical couplings of antibody fragments are also known.

The “light chains” of antibodies (immunoglobulins) from any vertebratespecies can be assigned to one of two clearly distinct types, calledkappa and lambda, based on the amino acid sequences of their constantdomains.

Depending on the amino acid sequence of the constant domain of theirheavy chains, immunoglobulins can be assigned to different classes.There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, andIgM, and several of these may be further divided into subclasses(isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA, and IgA2.

“Single-chain Fv” or “sFv” antibody fragments comprise the V_(H) andV_(L) domains of antibody, wherein these domains are present in a singlepolypeptide chain. Preferably, the Fv polypeptide further comprises apolypeptide linker between the V_(H) and V_(L) domains which enables thesFv to form the desired structure for antigen binding. For a review ofsFv, see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol.113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315(1994).

The term “diabodies” refers to small antibody fragments with twoantigen-binding sites, which fragments comprise a heavy-chain variabledomain (V_(H)) connected to a light-chain variable domain (V_(L)) in thesame polypeptide chain (V_(H)-V_(L)). By using a linker that is tooshort to allow pairing between the two domains on the same chain, thedomains are forced to pair with the complementary domains of anotherchain and create two antigen-binding sites. Diabodies are described morefully in, for example, EP 404,097; WO 93/11161; and Hollinger et al.,Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993).

An “isolated” antibody is one which has been identified and separatedand/or recovered from a component of its natural environment.Contaminant components of its natural environment are materials whichwould interfere with diagnostic or therapeutic uses for the antibody,and may include enzymes, hormones, and other proteinaceous ornonproteinaceous solutes. In preferred embodiments, the antibody will bepurified (1) to greater than 95% by weight of antibody as determined bythe Lowry method, and most preferably more than 99% by weight, (2) to adegree sufficient to obtain at least 15 residues of N-terminal orinternal amino acid sequence by use of a spinning cup sequenator, or (3)to homogeneity by SDS-PAGE under reducing or nonreducing conditionsusing Coomassie blue or, preferably, silver stain. Isolated antibodyincludes the antibody in situ within recombinant cells since at leastone component of the antibody's natural environment will not be present.Ordinarily, however, isolated antibody will be prepared by at least onepurification step.

The word “label” when used herein refers to a detectable compound orcomposition which is conjugated directly or indirectly to the antibodyso as to generate a “labeled” antibody. The label may be detectable byitself (e.g. radioisotope labels or fluorescent labels) or, in the caseof an enzymatic label, may catalyze chemical alteration of a substratecompound or composition which is detectable.

By “solid phase” is meant a non-aqueous matrix to which the antibody ofthe present invention can adhere. Examples of solid phases encompassedherein include those formed partially or entirely of glass (e.g.,controlled pore glass), polysaccharides (e.g., agarose),polyacrylamides, polystyrene, polyvinyl alcohol and silicones. Incertain embodiments, depending on the context, the solid phase cancomprise the well of an assay plate; in others it is a purificationcolumn (e.g., an affinity chromatography column). This term alsoincludes a discontinuous solid phase of discrete particles, such asthose described in U.S. Pat. No. 4,275,149.

A “liposome” is a small vesicle composed of various types of lipids,phospholipids and/or surfactant which is useful for delivery of a drug(such as a PRO polypeptide or antibody thereto) to a mammal. Thecomponents of the liposome are commonly arranged in a bilayer formation,similar to the lipid arrangement of biological membranes.

A “small molecule” is defined herein to have a molecular weight belowabout 500 Daltons.

“PRO317-associated disorder” refers to a pathological condition ordisease wherein PRO317 is over- or underexpressed. Such disordersinclude diseases of the female genital tract or of the endometrium of amammal, including hyperplasia, endometritis, endometriosis, wherein thepatient is at risk for infertility due to endometrial factor,endometrioma, and endometrial cancer, especially those diseasesinvolving abnormal bleeding such as a gynecological disease. They alsoinclude diseases involving angiogenesis, wherein the angiogenesisresults in a pathological condition, such as cancer involving solidtumors (the therapy for the disorder would result in decreasedvascularization and a decline in growth and metastasis of a variety oftumors). Alternatively, the angiogenesis may be beneficial, such as forischemia, especially coronary ischemia. Hence, these disorders includethose found in patients whose hearts are functioning but who have ablocked blood supply due to atherosclerotic coronary artery disease, andthose with a functioning but underperfused heart, including patientswith coronary arterial disease who are not optimal candidates forangioplasty and coronary artery by-pass surgery. The disorders alsoinclude diseases involving the kidney or originating from the kidneytissue, such as polycystic kidney disease and chronic and acute renalfailure.

TABLE 1 /*  *  * C-C increased from 12 to 15  * Z is average of EQ  * Bis average of ND  * match with stop is _M; stop-stop = 0; J (joker)match = 0  */ #define _M −8 /* value of a match with a stop */ int_day[26][26] = { /*  A B C D E F G H I J K L M N O P Q R S T U V W X Y Z*/ /* A */ { 2, 0, −2, 0, 0, −4, 1, −1, −1, 0, −1, −2, −1, 0, _M, 1, 0,−2, 1, 1, 0, 0, −6, 0, −3, 0}, /* B */ { 0, 3, −4, 3, 2, −5, 0, 1, −2,0, 0, −3, −2, 2, _M, −1, 1, 0, 0, 0, 0, −2, −5, 0, −3, 1}, /* C */ {−2,−4, 15, −5, −5, −4, −3, −3, −2, 0, −5, −6, −5, −4, _M, −3, −5, −4, 0,−2, 0, −2, −8, 0, 0, −5}, /* D */ {0, 3, −5, 4, 3, −6, 1, 1, −2, 0, 0,−4, −3, 2, _M, −1, 2, −1, 0, 0, 0, −2, −7, 0, −4, 2}, /* E */ {0, 2, −5,3, 4, −5, 0, 1, −2, 0, 0, −3, −2, 1, _M, −1, 2, −1, 0, 0, 0, −2, −7, 0,−4, 3}, /* F */ {−4, −5, −4, −6, −5, 9, −5, −2, 1, 0, −5, 2, 0, −4, _M,−5, −5, −4, −3, −3, 0, −1, 0, 0, 7, −5}, /* G */ { 1, 0, −3, 1, 0, −5,5, −2, −3, 0, −2, −4, −3, 0, _M, −1, −1, −3, 1, 0, 0, −1, −7, 0, −5, 0},/* H */ {−1, 1, −3, 1, 1, −2, −2, 6, −2, 0, 0, −2, −2, 2, _M, 0, 3, 2,−1, −1, 0, −2, −3, 0, 0, 2}, /* I */ {−1, −2, −2, −2, −2, 1, −3, −2, 5,0, −2, 2, 2, −2, _M, −2, −2, −2, −1, 0, 0, 4, −5, 0, −1, −2}, /* J */{0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, _M, 0, 0, 0, 0, 0, 0, 0, 0,0, 0, 0}, /* K */ {−1, 0, −5, 0, 0, −5, −2, 0, −2, 0, 5, −3, 0, 1, _M,−1, 1, 3, 0, 0, 0, −2, −3, 0, −4, 0}, /* L */ {−2, −3, −6, −4, −3, 2,−4, −2, 2, 0, −3, 6, 4, −3, _M, −3, −2, −3, −3 , −1, 0, 2, −2, 0, −1,−2} /* M */ {−1, −2, −5, −3, −2, 0, −3, −2, 2, 0, 0, 4, 6, −2, _M, −2,−1, 0, −2, −1, 0, 2, −4, 0, −2, −1}, /* N */ {0, 2, −4, 2, 1, −4, 0, 2,−2, 0, 1, −3, −2, 2, _M, −1, 1, 0, 1, 0, 0, −2, −4, 0, −2, 1}, /* O */{_M,_M,_M,_M,_M,_M,_M,_M,_M,_M,_M,_M,_M,_M,0,_M,_M,_M,_M,_M,_M,_M,_M,_M,_M,_M,}, /* P */ {1, −1, −3, −1, −1, −5,−1, 0, −2, 0, −1, −3, −2, −1, _M, 6, 0, 0, 1, 0, 0, −1, −6, 0, −5, 0},/* Q */ {0, 1, −5, 2, 2, −5, −1, 3, −2, 0, 1, −2, −1, 1, _M, 0, 4, 1,−1, −1, 0, −2, −5, 0, −4, 3}, /* R */ {−2, 0, −4, −1, −1, −4, −3, 2, −2,0, 3, −3, 0, 0, _M, 0, 1, 6, 0, −1, 0, −2, 2, 0, −4, 0}, /* S */ { 1, 0,0, 0, 0, −3, 1, −1, −1, 0, 0, −3, −2, 1, _M, 1, −1, 0, 2, 1, 0, −1, −2,0, −3, 0}, /* T */ { 1, 0, −2, 0, 0, −3, 0, −1, 0, 0, 0, −1, −1, 0, _M,0, −1, −1, 1, 3, 0, 0, −5, 0, −3, 0}, /* U */ {0, 0, 0, 0, 0, 0, 0, 0,0, 0, 0, 0, 0, 0, _M, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0}, /* V */ {0, −2,−2, −2, −2, −1, −1, −2, 4, 0, −2, 2, 2, −2, _M, −1, −2, −2, −1, 0, 0, 4,−6, 0, −2, −2}, /* W */ {−6, −5, −8, −7, −7, 0, −7, −3, −5, 0, −3, −2,−4, −4, _M, −6, −5, 2, −2, −5, 0, −6, 17, 0, 0, −6}, /* X */ {0, 0, 0,0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, _M, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0},/* Y */ {−3, −3, 0, −4, −4, 7, −5, 0, −1, 0, −4, −1, −2, −2, _M, −5, −4,−4, −3, −3, 0, −2, 0, 0, 10, −4}, /* Z */ { 0, 1, −5, 2, 3, −5, 0, 2,−2, 0, 0, −2, −1, 1, _M, 0, 3, 0, 0, 0, 0, −2, −6, 0, −4, 4}, }; /*  */#include <stdio.h> #include <ctype.h> #define MAXJMP  16 /* max jumps ina diag */ #define MAXGAP  24 /* don't continue to penalize gaps largerthan this */ #define JMPS 1024 /* max jmps in an path */ #define MX   4/* save if there's at least MX-1 bases since last jmp */ #define DMAT  3 /* value of matching bases */ #define DMIS   0 /* penalty formismatched bases */ #define DINS0   8 /* penalty for a gap */ #defineDINS1   1 /* penalty per base */ #define PINS0   8 /* penalty for a gap*/ #define PINS1   4 /* penalty per residue */ struct jmp { shortn[MAXJMP]; /* size of jmp (neg for dely) */ unsigned short x[MAXJMP]; /*base no. of jmp in seq x */ /* limits seq to 2{circumflex over ( )}16 −1*/ }; struct diag { int score; /* score at last jmp */ long offset; /*offset of prev block */ short ijmp; /* current jmp index */ struct jmpjp; /* list of jmps */ }; struct path { int spc; /* number of leadingspaces */ short n[JMPS]; /* size of jmp (gap) */ int x[JMPS]; /* loc ofjmp (last elem before gap) */ }; char *ofile; /* output file name */char *namex[2]; /* seq names: getseqs() */ char *prog; /* prog name forerr msgs */ char *seqx[2];   /* seqs: getseqs() */ int dmax; /* bestdiag: nw() */ int dmax0; /* final diag */ int dna; /* set if dna: main()*/ int endgaps; /* set if penalizing end gaps */ int gapx, gapy; /*total gaps in seqs */ int len0, len1; /* seq lens */ int ngapx, ngapy;/* total size of gaps */ int smax; /* max score: nw() */ int *xbm; /*bitmap for matching */ long offset; /* current offset in jmp file */struct diag *dx; /* holds diagonals */ struct path pp[2]; /* holds pathfor seqs */ char *calloc(), *malloc(), *index(), *strcpy(); char*getseq(), *g_calloc(); /* Needleman-Wunsch alignment program  *  *usage: progs file1 file2  * where file1 and file2 are two dna or twoprotein sequences.  * The sequences can be in upper- or lower-case anmay contain ambiguity  * Any lines beginning with ‘;’, ‘>’ or ‘<’ areignored  * Max file length is 65535 (limited by unsigned short x in thejmp struct)  * A sequence with ⅓ or more of its elements ACGTU isassumed to be DNA  * Output is in the file “align.out”  *  * The programmay create a tmp file in /tmp to hold info about traceback.  * Originalversion developed under BSD 4.3 on a vax 8650  */ #include “nw.h”#include “day.h” static _dbval[26] = {1,14,2,13,0,0,4,11,0,0,12,0,3,15,0,0,0,5,6,8,8,7,9,0,10,0 }; static_pbval[26] = { 1, 2|(1< <(‘D’-‘A’))|(1< <(‘N’-‘A’)), 4, 8, 16, 32, 64,128, 256, 0×FFFFFFF, 1< <10, 1< <11, 1< <12, 1< <13, 1< <14, 1< <15, 1<<16, 1< <17, 1< <18, 1< <19, 1< <20, 1< <21, 1< <22, 1< <23, 1< <24, 1<<25|(1< <(‘E’-‘A’))|(1< <(‘Q’-‘A’)) }; main(ac, av) main int ac; char*av[]; { prog = av[0]; if(ac != 3) { fprintf(stderr, “usage: %s file1file2\n”, prog); fprintf(stderr, “where file1 and file2 are two dna ortwo protein sequences.\n”); fprintf(stderr, “The sequences can be inupper- or lower-case\n”); fprintf(stderr, “Any lines beginning with ‘;’or ‘<’ are ignored\n”); fprintf(stderr, “Output is in the file\“align.out\”\n”); exit(1); } namex[0] = av[1]; namex[1] = av[2];seqx[0] = getseq(namex[0], &len0); seqx[1] = getseq(namex[1], &len1);xbm = (dna)? _dbval : _pbval; endgaps = 0; /* 1 to penalize endgaps */ofile = “align.out”; /* output file */ nw(); /* fill in the matrix, getthe possible jmps */ readjmps(); /* get the actual jmps */ print(); /*print stats, alignment */ cleanup(0); /* unlink any tmp files */ } /* dothe alignment, return best score: main()  * dna: values in Fitch andSmith, PNAS, 80, 1382-1386, 1983  * pro: PAM 250 values  * When scoresare equal, we prefer mismatches to any gap, prefer  * a new gap toextending an ongoing gap, and prefer a gap in seqx  * to a gap in seq y. */ nw() nw { char *px, *py;   /* seqs and ptrs */ int *ndely, *dely; /*keep track of dely */ int ndelx, delx; /* keep track of delx */ int*tmp; /* for swapping row0, row1 */ int mis; /* score for each type */int ins0, ins1; /* insertion penalties */ register id; /* diagonal index*/ register ij; /* jmp index */ register *col0, *col1; /* score forcurr, last row */ register xx, yy; /* index into seqs */ dx = (structdiag *)g_calloc(“to get diags”, len0+len1+1, sizeof(struct diag)); ndely= (int *)g_calloc(“to get ndely”, len1+1, sizeof(int)); dely = (int*)g_calloc(“to get dely”, len1+1, sizeof(int)); col0 = (int*)g_calloc(“to get col0”, len1+1, sizeof(int)); col1 = (int*)g_calloc(“to get col1”, len1+1, sizeof(int)); ins0 = (dna)? DINS0 :PINS0; ins1 = (dna)? DINS1 : PlNS1; smax = −10000; if (endgaps) { for(col0[0] = dely[0] = −ins0, yy = 1; yy <= len1; yy++) { col0[yy] =dely[yy] = col0[yy−1] − ins1; ndely[yy] = yy; } col0[0] = 0; /* WatermanBull Math Biol 84 */ } else for (yy= 1; yy <= len1; yy++) dely[yy] =−ins0; /* fill in match matrix  */ for (px = seqx[0], xx = 1; xx <=len0; px++, xx++) { /* initialize first entry in col  */ if (endgaps) {if (xx == 1) col1[0] = delx = −(ins0+ins1); else col1[0] = delx =col0[0]−ins1; ndelx = xx; } else { col1[0] = 0; delx = −ins0; ndelx = 0;} ...nw for (py = seqx[1], yy = 1; yy <= len1; py++, yy++) { mis =col0[yy−1]; if (dna) mis + = (xbm[*px−‘A’]&xbm[*py−‘A’])? DMAT : DMIS;else mis += _day[*px−‘A’][*py−‘A’]; /* update penalty for del in x seq; * favor new del over ongong del  * ignore MAXGAP if weighting endgaps */ if (endgaps || ndely[yy] < MAXGAP) { if (col0[yy] − ins0 >=dely[yy]) { dely[yy] = col0[yy] − (ins0+ins1); ndely[yy] = 1; } else {dely[yy] −= ins1; ndely[yy]++; } } else { if (col0[yy] − (ins0+ins1) >=dely[yy]) { dely[yy] = col0[yy] − (ins0+ins1); ndely[yy] = 1; } elsendely[yy]++; } /* update penalty for del in y seq;  * favor new del overongong del  */ if (endgaps || ndelx < MAXGAP) { if(col1[yy−1] − ins0 >=delx) { delx = col1[yy−1] − (ins0+ins1); ndelx = 1; } else { delx −=ins1; ndelx++; } } else { if (col1[yy−1] − (ins0+ins1) > = delx) { delx= col1[yy−1] − (ins0+ins1); ndelx = 1; } else ndelx+ +; } /* pick themaximum score; we're favoring  * mis over any del and delx over dely  */...nw id = xx − yy + len1 − 1; if (mis >= delx && mis >= dely[yy])col1[yy] = mis; else if (delx > = dely[yy]) { col1[yy] = delx; ij =dx[id].ijmp; if (dx[id].jp.n[0] && (!dna || (ndelx > = MAXJMP && xx >dx[id].jp.x[ij]+MX) || mis > dx[id].score+DINS0)) { dx[id].ijmp+ +; if(++ij >= MAXJMP) { writejmps(id); ij = dx[id].ijmp = 0; dx[id].offset =offset; offset += sizeof(struct jmp) + sizeof(offset); } }dx[id].jp.n[ij] = ndelx; dx[id].jp.x[ij] = xx; dx[id].score = delx; }else { col1[yy] = dely[yy]; ij = dx[id].ijmp; if (dx[id].jp.n[0] &&(!dna || (ndely[yy] > = MAXJMP && xx > dx[id].jp.x[ij]+MX) || mis >dx[id].score+DINS0)) { dx[id].ijmp++; if (++ij >= MAXJMP) {writejmps(id); ij = dx[id].ijmp = 0; dx[id].offset = offset; offset +=sizeof(struct jmp) + sizeof(offset); } } dx[id].jp.n[ij] =−ndely[yy];dx[id].jp.x[ij] = xx; dx[id].score = dely[yy]; } if (xx == len0 && yy <len1) { /* last col  */ if (endgaps) col1[yy] −= ins0+ins1*(len1−yy);if(col1[yy] > smax) { smax = col1[yy]; dmax = id; } } } if (endgaps &&xx < len0) col1[yy−1] −= ins0+ins1*(len0−xx); if (col1[yy−1] > smax) {smax = col1[yy−1]; dmax = id; } tmp = col0; col0 = col1; col1 = tmp; }(void) free((char *)ndely); (void) free((char *)dely); (void) free((char*)col0); (void) free((char *)col1); } /*  *  * print() -- only routinevisible outside this module  *  * static:  * getmat() -- trace back bestpath, count matches: print()  * pr_align() -- print alignment ofdescribed in array p[]: print()  * dumpblock() -- dump a block of lineswith numbers, stars: pr_align()  * nums() -- put out a number line:dumpblock()  * putline() -- put out a line (name, [num], seq, [num]):dumpblock()  * stars() - -put a line of stars: dumpblock()  *stripname() -- strip any path and prefix from a seqname  */ #include“nw.h” #define SPC  3 #define P_LINE 256 /* maximum output line */#define P_SPC  3 /* space between name or num and seq */ extern_day[26][26]; int olen; /* set output line length */ FILE *fx; /* outputfile */ print() print { int lx, ly, firstgap, lastgap;  /* overlap */ if((fx = fopen(ofile, “w”)) == 0) { fprintf(stderr, “ %s: can't write%s\n”, prog, ofile); cleanup(1); } fprintf(fx, “<first sequence: %s(length = %d)\n”, namex[0], len0); fprintf(fx, “<second sequence: %s(length = %d)\n”, namex[1], len1); olen = 60; lx = len0; ly = len1;firstgap = lastgap = 0; if (dmax < len1 − 1) { /* leading gap in x */pp[0].spc = firstgap = len1 − dmax − 1; ly −= pp[0].spc; } else if(dmax > len1 − 1) { /* leading gap in y */ pp[1].spc = firstgap = dmax −(len1 − 1); lx −= pp[1].spc; } if (dmax0 < len0 − 1) { /* trailing gapin x */ lastgap = len0 − dmax0 −1; lx −= lastgap; } else if (dmax0 >len0 − 1) { /* trailing gap in y */ lastgap = dmax0 − (len0 − 1); ly −=lastgap; } getmat(lx, ly, firstgap, lastgap); pr_align(); } /*  * traceback the best path, count matches  */ static getmat(lx, ly, firstgap,lastgap) getmat int lx, ly; /* “core” (minus endgaps) */ int firstgap,lastgap; /* leading trailing overlap */ { int nm, i0, i1, siz0, siz1;char outx[32]; double pct; register n0, n1; register char *p0, *p1; /*get total matches, score  */ i0 = i1 = siz0 = siz1 = 0; p0 = seqx[0] +pp[1].spc; p1 = seqx[1] + pp[0].spc; n0 = pp[1].spc + 1; n1 =pp[0].spc + 1; nm = 0; while ( *p0 && *p1 ) { if (siz0) { p1++; n1++;siz0−−; } else if (siz1) { p0+ +; n0+ +; siz1−−; } else { if(xbm[*p0−‘A’]&xbm[*p1−‘A’]) nm+ +; if (n0++ == pp[0].x[i0]) siz0 =pp[0].n[i0++]; if (nl++ == pp[1].x[i1]) siz1 = pp[1].n[il++]; p0+ +;p1++; } } /* pct homology:  * if penalizing endgaps, base is the shorterseq  * else, knock off overhangs and take shorter core  */ if (endgaps)lx = (len0 < len1)? len0 : len1; else lx = (lx < ly)? lx : ly; pct =100.*(double)nm/(double)lx; fprintf(fx, “\n”); fprintf(fx, “< %d match%sin an overlap of %d: %.2f percent similarity\n”, nm, (nm == 1)? “” :“es”, lx, pct); fprintf(fx, “<gaps in first sequence: %d”, gapx);...getmat if (gapx) { (void) sprintf(outx, “ (%d %s%s)”, ngapx, (dna)?“base”: “residue”, (ngapx == 1)? “”:“s”); fprintf(fx, “% s”, outx);fprintf(fx, “, gaps in second sequence: %d”, gapy); if (gapy) { (void)sprintf(outx, “(%d %s%s)”, ngapy, (dna)? “base”:“residue”, (ngapy == 1)?“”:“s”); fprintf(fx, “%s”, outx); } if (dna) fprintf(fx, “\n<score: %d(match = %d, mismatch = %d, gap penalty = %d + %d per base)\n”, smax,DMAT, DMIS, DINS0, DINS1); else fprintf(fx, “\n< score: %d (Dayhoff PAM250 matrix, gap penalty = %d + %d per residue)\n”, smax, PINS0, PINS1);if (endgaps) fprintf(fx, “<endgaps penalized. left endgap: %d %s%s,right endgap: %d %s%s\n”, firstgap, (dna)? “base” : “residue”, (firstgap== 1)? “” : “s”, lastgap, (dna)? “base” : “residue”, (lastgap == 1)? “”: “s”); else fprintf(fx, “<endgaps not penalized\n”); } static nm; /*matches in core -- for checking */ static lmax; /* lengths of strippedfile names */ static ij[2]; /* jmp index for a path */ static nc[2]; /*number at start of current line */ static ni[2]; /* current elem number-- for gapping */ static siz[2]; static char *ps[2]; /* ptr to currentelement */ static char *po[2]; /* ptr to next output char slot */ staticchar out[2][P_LINE]; /* output line */ static char star[P_LINE]; /* setby stars() */ /*  * print alignment of described in struct path pp[]  */static pr_align() pr_align { int nn; /* char count */ int more; registeri; for (i = 0, lmax = 0; i < 2++) { nn = stripname(namex[i]); if (nn >lmax) lmax = nn; nc[i] = 1; ni[i] = 1; siz[i] = ij[i] = 0; ps[i] =seqx[i]; po[i] = out[i]; } for (nn = nm = 0, more = 1; more;) {...pr_align for (i = more = 0; i < 2; i++) { /*  * do we have more ofthis sequence?  */ if (!*ps[i]) continue; more++; if (pp[i].spc) { /*leading space */ *po[i]++ = ‘ ’; pp[i].spc−−; } else if (siz[i]) { /* ina gap */ *po[i]++ = ‘−’; siz[i]−−; } else { /* we're putting a seqelement */ *po[i] = *ps[i]; if (islower(*ps[i])) *ps[i] =toupper(*ps[i]); po[i]++; ps[i]++; /*  * are we at next gap for thisseq?  */ if (ni[i] == pp[i].x[ij[i]]) { /*  * we need to merge all gaps * at this location  */ siz[i] == pp[i].n[ij[i]++]; while (ni[i] ==pp[i].x[ij[i]]) siz[i] += pp[i].n[ij[i]++]; } ni[i]++; } } if (++nn ==olen || !more && nn) { dumpblock(); for (i = 0; i < 2; i++) po[i] =out[i]; nn = 0; } } } /*  * dump a block of lines, including numbers,stars: pr_align()  */ static dumpblock() dumpblock { register i; for(i =0; i < 2; i++) *po[i]−− = ‘\0’; ...dumpblock (void) putc(‘\n’, fx); for(i = 0; i < 2; i++) { if (*out[i] && (*out[i] != ‘ ’ || *(po[i]) != ‘’)) { if (i == 0) nums(i); if (i == 0 && *out[1]) stars(); putline(i);if (i == 0 && *out[1]) fprintf(fx, star); if (i == 1) nums(i); } } }/* * put out a number line: dumpblock()  */ static nums(ix) numsint  ix; /* index in out[] holding seq line */ { char nline[P_LINE];register i, j; register char *pn, *px, *py; for(pn = nline, i = 0; i <lmax+P_SPC; i++, pn++) *pn = ‘ ’; for (i = nc[ix], py = out[ix]; *py;py++, pn++) { if (*py == ‘ ’ || *py == ‘−’); *pn = ‘ ’; else { if (i%10== 0 || (i == 1 && nc[ix] != 1)) { j = (i < 0)? −i : i; for (px = pn; j;j/= 10, px−−) *px = j%10 + ‘0’; if (i < 0) *px = ‘−’; } else *pn = ‘ ’;i+ +; } } *pn = ‘\0’; nc[ix] = i; for (pn = nline; *pn; pn+ +) (void)putc(*pn, fx); (void) putc(‘\n’, fx); } /*  * put out a line (name,[num], seq. [num]): dumpblock()  */ static putline(ix) putline int   ix;{ ...putline int i; register char *px; for (px = namex[ix], i = 0; *px&& *px != ‘:’; px++, i++) (void) putc(*px, fx); for (;i < lmax+P_SPC;i++) (void) putc(‘ ’, fx); /* these count from 1:  * ni[] is currentelement (from 1)  * nc[] is number at start of current line  */ for (px= out[ix]; *px; px+ +) (void) putc(*px&0x7F, fx); (void) putc(‘\n’, fx);} /*  * put a line of stars (seqs always in out[0], out[1]): dumpblock() */ static stars() stars { int i; register char *p0, *p1, cx, *px; if(!*out[0] || (*out[0] == ‘ ’ && *(p0[0]) == ‘ ’) || !*out[1] || (*out[1]== ‘ ’ && *(po[1]) == ‘ ’)) return; px = star; for (i = lmax+P_ SPC; i;i−−) *px++ = ‘ ’; for (p0 = out[0], p1 = out[1]; *p0 && *p1; p0++, p1++){ if (isalpha(*p0) && isalpha(*p1)) { if (xbm[*p0−‘A’]&xbm[*p1−‘A’]) {cx = ‘*’; nm+ +; } else if (!dna && _day[*p0− ‘A’][*p1−‘A’] > 0) cx =‘.’; else cx = ‘ ’; } else cx = ‘ ’; *px++ = cx; } *px++ = ‘\n’; *px =‘\0’; } /*  * strip path or prefix from pn, return len: pr_align()  */static stripname(pn) stripname char *pn; /* file name (may be path) */ {register char *px, *py; py = 0; for (px = pn; *px; px++) if (*px == ‘/’)py = px + 1; if (py) (void) strcpy(pn, py); return(strlen(pn)); } /*  *cleanup() -- cleanup any tmp file  * getseq() -- read in seq, set dna,len, maxlen  * g_calloc() -- calloc() with error checkin  * readjmps()-- get the good jmps, from tmp file if necessary  * writejmps() -- writea filled array of jmps to a tmp file: nw()  */ #include “nw.h” #include<sys/file.h> char *jname = “/tmp/homgXXXXXX”; /* tmp file for jmps */FILE *fj; int cleanup(); /* cleanup tmp file */ long lseek(); /*  *remove any tmp file if we blow  */ cleanup(i) cleanup int i; { if (fj)(void) unlink(jname); exit(i); } /*  * read, return ptr to seq, set dna,len, maxlen  * skip lines starting with ‘;’, ‘<’, or ‘>’  * seq in upperor lower case  */ char * getseq(file, len) getseq char *file; /* filename */ int *len; /* seq len */ { char line[1024], *pseq; register char*px, *py; int natgc, tlen; FILE *fp; if ((fp = fopen(file, “r”)) == 0) {fprintf(stderr, “%s: can't read %s\n”, prog, file); exit(1); } tlen =natgc = 0; while (fgets(line, 1024, fp)) { if (*line == ‘;’ || *line ==‘<’ || *line == ‘>’) continue; for (px = line; *px != ‘\n’; px+ +) if(isupper(*px) || islower(*px)) tlen++; } if ((pseq =malloc((unsigned)(tlen+ 6))) == 0) { fprintf(stderr, “%s: malloc()failed to get %d bytes for %s\n”, prog, tlen+6, file); exit(1); }pseq[0] = pseq[1] = pseq[2] = pseq[3] = ‘\0’; ...getseq py = pseq + 4;*len = tlen; rewind(fp); while (fgets(line, 1024, fp)) { if (*line ==‘;’ || *line == ‘<’ || *line == ‘>’) continue; for (px = line; *px !=‘\n’; px++) { if (isupper(*px)) *py++ = *px; else if (islower(*px))*py+ + = toupper(*px); if (index(“ATGCU” , *(py−1))) natgc+ +; } } *py++= ‘\0’; *py = ‘\0’; (void) fclose(fp); dna = natgc > (tlen/3);return(pseq+4); } char * g_calloc(msg, nx, sz) g_calloc char *msg; /*program, calling routine */ int nx, sz; /* number and size of elements*/ { char *px, *calloc(); if ((px = calloc((unsigned)nx, (unsigned)sz))== 0) { if (*msg) { fprintf(stderr, “%s: g_calloc() failed %s (n= %d,sz= %d)\n”, prog, msg, nx, sz); exit(1); } } return(px); } /*  * getfinal jmps from dx[] or tmp file, set pp[], reset dmax: main()  */readjmps() readjmps { int fd = −1; int siz, i0, i1; register i, j, xx;if (fj) { (void) fclose(fj); if ((fd = open(jname, O_RDONLY, 0)) < 0) {fprintf(stderr, “%s: can't open() %s\n”, prog, jname); cleanup(1); } }for (i = i0 = i1 = 0, dmax0 = dmax, xx = len0; ;i++) { while (1) { for(j = dx[dmax].ijmp; j >= 0 && dx[dmax].jp.x[j] >= xx; j−−) ; ...readjmpsif (j < 0 && dx[dmax].offset && fj) { (void) lseek(fd, dx[dmax].offset,0); (void) read(fd, (char *)&dx[dmax].jp, sizeof(struct jmp)); (void)read(fd, (char *)&dx[dmax].offset, sizeof(dx[dmax].offset));dx[dmax].ijmp = MAXJMP−1; } else break; } if (i > = JMPS) {fprintf(stderr, “%s: too many gaps in alignment\n”, prog); cleanup(1); }if (j >= 0) { siz = dx[dmax].jp.n[j]; xx = dx[dmax].jp.x[j]; dmax +=siz; if (siz < 0) { /* gap in second seq */ pp[1].n[il] = −siz; xx +=siz; /* id = xx − yy + len1 − 1  */ pp[1].x[il] = xx − dmax + len1 − 1;gapy+ +; ngapy −= siz; /* ignore MAXGAP when doing endgaps */ siz =(−siz < MAXGAP || endgaps)? −siz : MAXGAP; il++; } else if (siz > 0) {/* gap in first seq */ pp[0] .n[i0] = siz; pp[0] .x[i0] = xx; gapx+ +;ngapx += siz; /* ignore MAXGAP when doing endgaps */ siz = (siz < MAXGAP|| endgaps)? siz : MAXGAP; i0+ +; } } else break; } /* reverse the orderof jmps  */ for (j = 0, i0−−; j < i0; j++, i0−−) { i = pp[0].n[j];pp[0].n[j] = pp[0].n[i0]; pp[0].n[i0] = i; i = pp[0].x[j]; pp[0].x[j] =pp[0].x[i0]; pp[0].x[i0] = i; } for (j = 0, i1−−; j < i1; j++, i1−−) { i= pp[1].n[j]; pp[1].n[j] = pp[1].n[i1]; pp[1].n[i1] = i; i = pp[1].x[j];pp[1].x[j] = pp[1].x[i1]; pp[1].x[i1] = i; } if (fd > = 0) (void)close(fd); if (fj) { (void) unlink(jname); fj = 0; offset = 0; } } /*  *write a filled jmp struct offset of the prev one (if any): nw()  */writejmps(ix) writejmps int ix; { char *mktemp(); if (!fj) { if(mktemp(jname) < 0) { fprintf(stderr, “%s: can't mktemp() %s\n”, prog,jname); cleanup(1); } if ((fj = fopen(jname, “w”)) == 0) {fprintf(stderr, “%s: can't write %s\n”, prog, jname); exit(1); } }(void) fwrite((char *)&dx[ix].jp, sizeof(struct jmp), 1, fj); (void)fwrite((char *)&dx[ix].offset, sizeof(dx[ix].offset), 1, fj); }

TABLE 2 PRO XXXXXXXXXXXXXXX (Length = 15 amino acids) ComparisonXXXXXYYYYYYY (Length = 12 amino acids) Protein % amino acid sequenceidentity = (the number of identically matching amino acid residuesbetween the two polypeptide sequences as determined by ALIGN-2) dividedby (the total number of amino acid residues of the PRO polypeptide) = 5divided by 15 = 33.3%

TABLE 3 PRO XXXXXXXXXX (Length = 10 amino acids) ComparisonXXXXXYYYYYYZZYZ (Length = 15 amino acids) Protein % amino acid sequenceidentity = (the number of identically matching amino acid residuesbetween the two polypeptide sequences as determined by ALIGN-2) dividedby (the total number of amino acid residues of the PRO polypeptide) = 5divided by 10 = 50%

TABLE 4 PRO-DNA NNNNNNNNNNNNNN (Length = 14 nucleotides) ComparisonNNNNNNLLLLLLLLLL (Length = 16 nucleotides) DNA % nucleic acid sequenceidentity = (the number of identically matching nucleotides between thetwo nucleic acid sequences as determined by ALIGN-2) divided by (thetotal number of nucleotides of the PRO-DNA nucleic acid sequence) = 6divided by 14 = 42.9%

TABLE 5 PRO-DNA NNNNNNNNNNNN (Length = 12 nucleotides) Comparison DNANNNNLLLVV (Length = 9 nucleotides) DNA % nucleic acid sequence identity= (the number of identically matching nucleotides between the twonucleic acid sequences as determined by ALIGN-2) divided by (the totalnumber of nucleotides of the PRO-DNA nucleic acid sequence) = 4 dividedby 12 = 33.3%

II. Compositions and Methods of the Invention

A. Full-Length PRO Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO polypeptides. In particular, cDNAs encoding various PROpolypeptides have been identified and isolated, as disclosed in furtherdetail in the Examples below. It is noted that proteins produced inseparate expression rounds may be given different PRO numbers but theUNQ number is unique for any given DNA and the encoded protein, and willnot be changed. However, for sake of simplicity, in the presentspecification the protein encoded by the full length native nucleic acidmolecules disclosed herein as well as all further native homologues andvariants included in the foregoing definition of PRO, will be referredto as “PRO/number”, regardless of their origin or mode of preparation.

As disclosed in the Examples below, various cDNA clones have beendeposited with the ATCC. The actual nucleotide sequences of those clonescan readily be determined by the skilled artisan by sequencing of thedeposited clone using routine methods in, the art. The predicted aminoacid sequence can be determined from the nucleotide sequence usingroutine skill. For the PRO polypeptides and encoding nucleic acidsdescribed herein, Applicants have identified what is believed to be thereading frame best identifiable with the sequence information availableat the time.

1. Full-Length PRO211 and PRO217 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO211 and PRO217. In particular, Applicants have identified andisolated cDNA encoding PRO211 and PRO217 polypeptides, as disclosed infurther detail in the Examples below. Using BLAST (FastA format)sequence alignment computer programs, Applicants found that cDNAsequences encoding full-length native sequence PRO211 and PRO217 havehomologies to known proteins having EGF-like domains. Specifically, thecDNA sequence DNA32292-1131 (FIG. 1, SEQ ID NO:1) has certain identifyand a Blast score of 209 with PAC6_RAT and certain identify and a Blastscore of 206 with Fibulin-1, isoform c precursor. The cDNA sequenceDNA33094-1131 (FIG. 3, SEQ ID NO:3) has 36% identity and a Blast scoreof 336 with eastern newt tenascin, and 37% identity and a Blast score of331 with human tenascin-X precursor. Accordingly, it is presentlybelieved that PRO211 and PRO217 polypeptides disclosed in the presentapplication are newly identified members of the EGF-like family andpossesses properties typical of the EGF-like protein family.

2. Full-Length PRO230 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO230. In particular, Applicants have identified and isolated cDNAencoding a PRO230 polypeptide, as disclosed in further detail in theExamples below. Using known programs such as BLAST and FastA sequencealignment computer programs, Applicants found that a cDNA sequenceencoding full-length native sequence PRO230 has 48% amino acid identitywith the rabbit tubulointerstitial nephritis antigen precursor.Accordingly, it is presently believed that PRO230 polypeptide disclosedin the present application is a newly identified member of thetubulointerstitial nephritis antigen family and possesses the ability tobe recognized by human autoantibodies in certain forms oftubulointerstitial nephritis.

3. Full-Length PRO232 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO232. In particular, Applicants have identified and isolated cDNAencoding a PRO232 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that a portion of the full-length nativesequence PRO232 (shown in FIG. 9 and SEQ ID NO:18) has 35% sequenceidentity with a stem cell surface antigen from Gallus gallus.Accordingly, it is presently believed that the PRO232 polypeptidedisclosed in the present application may be a newly identified stem cellantigen.

4. Full-Length PRO187 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO187. In particular, Applicants have identified and isolated cDNAencoding a PRO187 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that a fill-length native sequence PRO187(shown in FIG. 15) has 74% amino acid sequence identity and BLAST scoreof 310 with various androgen-induced growth factors and FGF-8.Accordingly, it is presently believed that PRO187 polypeptide disclosedin the present application is a newly identified member of the FGF-8protein family and may possess identify activity or property typical ofthe FGF-8-like protein family.

5. Full-Length PRO265 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO265. In particular, Applicants have identified and isolated cDNAencoding a PRO265 polypeptide, as disclosed in further detail in theExamples below. Using programs such as BLAST and FastA sequencealignment computer programs, Applicants found that various portions ofthe PRO265 polypeptide have significant homology with the fibromodulinprotein and fibromodulin precursor protein. Applicants have also foundthat the DNA encoding the PRO265 polypeptide has significant homologywith platelet glycoprotein V, a member of the leucine rich relatedprotein family involved in skin and wound repair. Accordingly, it ispresently believed that PRO265 polypeptide disclosed in the presentapplication is a newly identified member of the leucine rich repeatfamily and possesses protein protein binding capabilities, as well as beinvolved in skin and wound repair as typical of this family.

6. Full-Length PRO219 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO219. In particular, Applicants have identified and isolated cDNAencoding a PRO219 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that various portions of the PRO219polypeptide have significant homology with the mouse and humanmatrilin-2 precursor polypeptides. Accordingly, it is presently believedthat PRO219 polypeptide disclosed in the present application is relatedto the matrilin-2 precursor polypeptide.

7. Full-Length PRO246 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO246. In particular, Applicants have identified and isolated cDNAencoding a PRO246 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that a portion of the PRO246 polypeptide hassignificant homology with the human cell surface protein HCAR.Accordingly, it is presently believed that PRO246 polypeptide disclosedin the present application may be a newly identified membrane-boundvirus receptor or tumor cell-specific antigen.

8. Full-Length PRO228 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO228. In particular, Applicants have identified and isolated cDNAencoding a PRO228 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that various portions of the PRO228polypeptide have significant homology with the EMR1 protein. Applicantshave also found that the DNA encoding the PRO228 polypeptide hassignificant homology with latrophilin, macrophage-restricted cellsurface glycoprotein, B0457.1 and leucocyte antigen CD97 precursor.Accordingly, it is presently believed that PRO228 polypeptide disclosedin the present application is a newly identified member of the seventransmembrane superfamily and possesses characteristics and functionalproperties typical of this family. In particular, it is believed thatPRO228 is a new member of the subgroup within this family to which CD97and EMR1 belong.

9. Full-Length PRO533 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO533. In particular, Applicants have identified and isolated cDNAencoding a PRO533 polypeptide, as disclosed in further detail in theExamples below. Using BLAST-2 and FastA sequence alignment computerprograms, Applicants found that a full-length native sequence PRO533(shown in FIG. 22 and SEQ ID NO:59) has a Blast score of 509 and 53%amino acid sequence identity with fibroblast growth factor (FGF).Accordingly, it is presently believed that PRO533 disclosed in thepresent application is a newly identified member of the fibroblastgrowth factor family and may possess activity typical of suchpolypeptides.

10. Full-Length PRO245 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO245. In particular, Applicants have identified and isolated cDNAencoding a PRO245 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that a portion of the amino acid sequence ofthe PRO245 polypeptide has 60% amino acid identity with the human c-mybprotein. Accordingly, it is presently believed that the PRO245polypeptide disclosed in the present application may be a newlyidentified member of the transmembrane protein tyrosine kinase family.

11. Full-Length PRO220, PRO221 and PRO227 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO220, PRO221 and PRO227. In particular, Applicants have identifiedand isolated cDNAs encoding a PRO220, PRO221 and PRO227 polypeptide,respectively, as disclosed in further detail in the Examples below.Using BLAST and FastA sequence alignment computer programs, PRO220 hasamino acid identity with the amino acid sequence of a leucine richprotein wherein the identity is 87%. PRO220 additionally has amino acididentity with the neuronal leucine rich protein wherein the identity is55%. The neuronal leucine rich protein is further described in Taguchi,et al., Mol. Brain Res., 35:31-40 (1996).

PRO221 has amino acid identity with the SLIT protein precursor, whereindifferent portions of these two proteins have the respective percentidentities of 39%, 38%, 34%, 31%, and 30%.

PRO227 has amino acid identity with the amino acid sequence of plateletglycoprotein V precursor. The same results were obtained for humanglycoprotein V. Different portions of these two proteins show thefollowing percent identities of 30%, 28%, 28%, 31%, 35%, 39% and 27%.

Accordingly, it is presently believed that PRO220, PRO221 and PRO227polypeptides disclosed in the present application are newly identifiedmembers of the leucine rich repeat protein superfamily and that eachpossesses protein-protein binding capabilities typical of the leucinerich repeat protein superfamily. It is also believed that they havecapabilities similar to those of SLIT, the leucine rich repeat proteinand human glycoprotein V.

12. Full-Length PRO258 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO258. In particular, Applicants have identified and isolated cDNAencoding a PRO258 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that various portions of the PRO258polypeptide have significant homology with the CRTAM and poliovirusreceptors. Accordingly, it is presently believed that PRO258 polypeptidedisclosed in the present application is a newly identified member of theIg superfamily and possesses virus receptor capabilities or regulatesimmune function as typical of this family.

13. Full-Length PRO266 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO266. In particular, Applicants have identified and isolated cDNAencoding a PRO266 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that various portions of the PRO266polypeptide have significant homology with the SLIT protein fromDrosophilia. Accordingly, it is presently believed that PRO266polypeptide disclosed in the present application is a newly identifiedmember of the leucine rich repeat family and possesses ligand-ligandbinding activity and neuronal development typical of this family. SLIThas been shown to be useful in the study and treatment of Alzheimer'sdisease, supra, and thus, PRO266 may have involvement in the study andcure of this disease.

14. Full-Length PRO269 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO269. In particular, Applicants have identified and isolated cDNAencoding a PRO269 polypeptide, as disclosed in further detail in theExamples below. Using BLAST, FastA and sequence alignment computerprograms, Applicants found that the amino acid sequence encoded bynucleotides 314 to 1783 of the full-length native sequence PRO269 (shownin FIG. 35 and SEQ ID NO:95) has significant homology to human urinarythrombomodulin and various thrombomodulin analogues respectively, towhich it was aligned. Accordingly, it is presently believed that PRO269polypeptide disclosed in the present application is a newly identifiedmember of the thrombomodulin family.

15. Full-Length PRO287 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO287. In particular, Applicants have identified and isolated cDNAencoding a PRO287 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that various portions of the PRO287polypeptide have significant homology with the type 1 procollagenC-proteinase enhancer protein precursor and type 1 procollagenC-proteinase enhancer protein. Accordingly, it is presently believedthat PRO287 polypeptide disclosed in the present application is a newlyidentified member of the C-proteinase enhancer protein family.

16. Full-Length PRO214 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO214. In particular, Applicants have identified and isolated cDNAencoding a PRO214 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that a full-length native sequence PRO214polypeptide (shown in FIG. 40 and SEQ ID NO:109) has 49% amino acidsequence identity with HT protein, a known member of the EGF-family. Thecomparison resulted in a BLAST score of 920, with 150 matchingnucleotides. Accordingly, it is presently believed that the PRO214polypeptide disclosed in the present application is a newly identifiedmember of the family comprising EGF domains and may possess activitiesor properties typical of the EGF-domain containing family.

17. Full-Length PRO317 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO317. In particular, cDNA encoding a PRO317 polypeptide has beenidentified and isolated, as disclosed in further detail in the Examplesbelow. Using BLAST™ and FastA™ sequence alignment computer programs, itwas found that a full-length native-sequence PRO317 (shown in FIG. 42and SEQ ID NO:114) has 92% amino acid sequence identity with EBAF-1.Further, it is closely aligned with many other members of theTGF-superfamily.

Accordingly, it is presently believed that PRO317 disclosed in thepresent application is a newly identified member of the TGF-superfamilyand may possess properties that are therapeutically useful in conditionsof uterine bleeding, etc. Hence, PRO317 may be useful in diagnosing ortreating abnormal bleeding involved in gynecological diseases, forexample, to avoid or lessen the need for a hysterectomy. PRO317 may alsobe useful as an agent that affects angiogenesis in general, so PRO317may be useful in anti-tumor indications, or conversely, in treatingcoronary ischemic conditions.

Library sources reveal that ESTs used to obtain the consensus DNA forgenerating PRO317 primers and probes were found in normal tissues(uterus, prostate, colon, and pancreas), in several tumors (colon, brain(twice), pancreas, and mullerian cell), and in a heart with ischemia.PRO317 has shown up in several tissues as well, but it does look to havea greater concentration in uterus. Hence, PRO317 may have a broader useby the body than EBAF-1. It is contemplated that, at least for someindications, PRO317 may have opposite effects from EBAF-1.

18. Full-Length PRO301 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO301. In particular, Applicants have identified and isolated cDNAencoding a PRO301 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that a full-length native sequence PRO301(shown in FIG. 44 and SEQ ID NO:119) has a Blast score of 246corresponding to 30% amino acid sequence identity with human A33 antigenprecursor. Accordingly, it is presently believed that PRO301 disclosedin the present application is a newly identified member of the A33antigen protein family and may be expressed in human neoplastic diseasessuch as colorectal cancer.

19. Full-Length PRO224 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO224. In particular, Applicants have identified and isolated cDNAencoding a PRO224 polypeptide, as disclosed in further detail in theExamples below. Using known programs such as BLAST and FastA sequencealignment computer programs, Applicants found that full-length nativePRO224 (FIG. 46, SEQ ID NO:127) has amino acid identity withapolipoprotein E receptor 2906 from homo sapiens. The alignments ofdifferent portions of these two polypeptides show amino acid identitiesof 37%, 36%, 30%, 44%, 44% and 28% respectively. Full-Length nativePRO224 (FIG. 46, SEQ ID NO:127) also has amino acid identity with verylow-density lipoprotein receptor precursor from gall. The alignments ofdifferent portions of these two polypeptides show amino acid identitiesof 38%, 37%, 42%, 33%, and 37% respectively. Additionally, full-lengthnative PRO224 (FIG. 46, SEQ ID NO:127) has amino acid identity with thechicken oocyte receptor P95 from Gallus gallus. The alignments ofdifferent portions of these two polypeptides show amino acid identitiesof 38%, 37%, 42%, 33%, and 37% respectively. Moreover, full-lengthnative PRO224 (FIG. 46, SEQ ID NO:127) has amino acid identity with verylow density lipoprotein receptor short form precursor from humans. Thealignments of different portions of these two polypeptides show aminoacid identities of 32%, 38%, 34%, 45%, and 31%, respectively.Accordingly, it is presently believed that PRO224 polypeptide disclosedin the present application is a newly identified member of the lowdensity lipoprotein receptor family and possesses the structuralcharacteristics required to have the functional ability to recognize andendocytose low density lipoproteins typical of the low densitylipoprotein receptor family. (The alignments described above used thefollowing scoring parameters: T=7, S+65, S2=36, Matrix: BLOSUM62.)

20. Full-Length PRO222 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO222. In particular, Applicants have identified and isolated cDNAencoding a PRO222 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that a sequence encoding full-length nativesequence PRO222 (shown in FIG. 48 and SEQ ID NO:132) has 25-26% aminoacid identity with mouse complement factor h precursor, has 27-29% aminoacid identity with complement receptor, has 25-47% amino acid identitywith mouse complement C3b receptor type 2 long form precursor, has 40%amino acid identity with human hypothetical protein kiaa0247.Accordingly, it is presently believed that PRO222 polypeptide disclosedin the present application is a newly identified member of thecomplement receptor family and possesses activity typical of thecomplement receptor family.

21. Full-Length PRO234 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO234. In particular, Applicants have identified and isolated cDNAencoding a PRO234 polypeptide, as disclosed in further detail in theExamples below. Using BLAST (FastA-format) sequence alignment computerprograms, Applicants found that a cDNA sequence encoding full-lengthnative sequence PRO234 has 31% identity and Blast score of 134 withE-selectin precursor. Accordingly, it is presently believed that thePRO234 polypeptides disclosed in the present application are newlyidentified members of the lectin/selectin family and possess activitytypical of the lectin/selectin family.

22. Full-Length PRO231 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO231. In particular, Applicants have identified and isolated cDNAencoding a PRO231 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that the full-length native sequence PRO231polypeptide (shown in FIG. 52 and SEQ ID NO:142) has 30% and 31% aminoacid identity with human and rat prostatic acid phosphatase precursorproteins, respectively. Accordingly, it is presently believed that thePRO231 polypeptide disclosed in the present application may be a newlyidentified member of the acid phosphatase protein family.

23. Full-Length PRO229 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO229. In particular, Applicants have identified and isolated cDNAencoding a PRO229 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that various portions of the PRO229polypeptide have significant homology with antigen wc1.1, M130 antigen,T cell surface glycoprotein CD6. It also is related to Sp-alpha.Accordingly, it is presently believed that PRO229 polypeptide disclosedin the present application is a newly identified member of the familycontaining scavenger receptor homology, a sequence motif found in anumber of proteins involved in immune function and thus possesses immunefunction and/or segments which resist degradation, typical of thisfamily.

24. Full-Length PRO238 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO238. In particular, Applicants have identified and isolated cDNAencoding a PRO238 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that various portions of the PRO238polypeptide have significant homology with reductases, includingoxidoreductase and fatty acyl-CoA reductase. Accordingly, it ispresently believed that PRO238 polypeptide disclosed in the presentapplication is a newly identified member of the reductase family andpossesses reducing activity typical of the reductase family.

25. Full-Length PRO233 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO233. In particular, Applicants have identified and isolated cDNAencoding a PRO233 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that various portions of the PRO233polypeptide have significant homology with the reductase protein.Applicants have also found that the DNA encoding the PRO233 polypeptidehas significant homology with proteins from Caenorhabditis elegans.Accordingly, it is presently believed that PRO233 polypeptide disclosedin the present application is a newly identified member of the reductasefamily and possesses the ability to effect the redox state of the celltypical of the reductase family.

26. Full-Length PRO223 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO223. In particular, Applicants have identified and isolated cDNAencoding a PRO223 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that the PRO223 polypeptide has significanthomology with various serine carboxypeptidase polypeptides. Accordingly,it is presently believed that PRO223 polypeptide disclosed in thepresent application is a newly identified serine carboxypeptidase.

27. Full-Length PRO235 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO235. In particular, Applicants have identified and isolated cDNAencoding a PRO235 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that various portions of the PRO235polypeptide have significant homology with the various plexin proteins.Accordingly, it is presently believed that PRO235 polypeptide disclosedin the present application is a newly identified member of the plexinfamily and possesses cell adhesion properties typical of the plexinfamily.

28. Full-Length PRO236 and PRO262 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO236 and PRO262. In particular, Applicants have identified andisolated cDNA encoding PRO236 and PRO262 polypeptides, as disclosed infurther detail in the Examples below. Using BLAST and FastA sequencealignment computer programs, Applicants found that various portions ofthe PRO236 and PRO262 polypeptides have significant homology withvarious β-galactosidase and β-galactosidase precursor polypeptides.Accordingly, it is presently believed that the PRO236 and PRO262polypeptides disclosed in the present application are newly identifiedβ-galactosidase homologs.

29. Full-Length PRO239 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO239. In particular, Applicants have identified and isolated cDNAencoding a PRO239 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that various portions of the PRO239polypeptide have significant homology with densin proteins. Accordingly,it is presently believed that PRO239 polypeptide disclosed in thepresent application is a newly identified member of the densin familyand possesses cell adhesion and the ability to effect synaptic processesas is typical of the densin family.

30. Full-Length PRO257 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO257. In particular, Applicants have identified and isolated cDNAencoding a PRO257 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that various portions of the PRO257polypeptide have significant homology with the ebnerin precursor andebnerin protein. Accordingly, it is presently believed that PRO257polypeptide disclosed in the present application is a newly identifiedprotein member which is related to the ebnerin protein.

31. Full-Length PRO260 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO260. In particular, Applicants have identified and isolated cDNAencoding a PRO260 polypeptide, as disclosed in further detail in theExamples below. Using programs such as BLAST and FastA sequencealignment computer programs, Applicants found that various portions ofthe PRO260 polypeptide have significant homology with thealpha-1-fucosidase precursor. Accordingly, it is presently believed thatPRO260 polypeptide disclosed in the present application is a newlyidentified member of the fucosidase family and possesses enzymaticactivity related to fucose residues typical of the fucosidase family.

32. Full-Length PRO263 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO263. In particular, Applicants have identified and isolated cDNAencoding a PRO263 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that various portions of the PRO263polypeptide have significant homology with the CD44 antigen and relatedproteins. Accordingly, it is presently believed that PRO263 polypeptidedisclosed in the present application is a newly identified member of theCD44 antigen family and possesses at least one of the propertiesassociated with these antigens, i.e., cancer and HIV marker, cell-cellor cell-matrix interactions, regulating cell traffic, lymph node homing,transmission of growth signals, and presentation of chemokines andgrowth factors to traveling cells.

33. Full-Length PRO270 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO270. In particular, Applicants have identified and isolated cDNAencoding a PRO270 polypeptide, as disclosed in further detail in theExamples below. Using BLAST, FastA and sequence alignment computerprograms, Applicants found that various portions of the PRO270polypeptide have significant homology with various thioredoxin proteins.Accordingly, it is presently believed that PRO270 polypeptide disclosedin the present application is a newly identified member of thethioredoxin family and possesses the ability to effectreduction-oxidation (redox) state typical of the thioredoxin family.

34. Full-Length PRO271 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO271. In particular, Applicants have identified and isolated cDNAencoding a PRO271 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that the PRO271 polypeptide has significanthomology with various link proteins and precursors thereof. Accordingly,it is presently believed that PRO271 polypeptide disclosed in thepresent application is a newly identified link protein homolog.

35. Full-Length PRO272 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO272. In particular, Applicants have identified and isolated cDNAencoding a PRO272 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that various portions of the PRO272polypeptide have significant homology with the human reticulocalbinprotein and its precursors. Applicants have also found that the DNAencoding the PRO272 polypeptide has significant homology with the mousereticulocalbin precursor protein. Accordingly, it is presently believedthat PRO272 polypeptide disclosed in the present application is a newlyidentified member of the reticulocalbin family and possesses the abilityto bind calcium typical of the reticulocalbin family.

36. Full-Length PRO294 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO294. In particular, Applicants have identified and isolated cDNAencoding a PRO294 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that various portions of the PRO294polypeptide have significant homology with the various portions of anumber of collagen proteins. Accordingly, it is presently believed thatPRO294 polypeptide disclosed in the present application is a newlyidentified member of the collagen family.

37. Full-Length PRO295 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO295. In particular, Applicants have identified and isolated cDNAencoding a PRO295 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that various portions of the PRO295polypeptide have significant homology with integrin proteins.Accordingly, it is presently believed that PRO295 polypeptide disclosedin the present application is a newly identified member of the integrinfamily and possesses cell adhesion typical of the integrin family.

38. Full-Length PRO293 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO293. In particular, Applicants have identified and isolated cDNAencoding a PRO293 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that portions of the PRO293 polypeptide havesignificant homology with the neuronal leucine rich repeat proteins 1and 2, (NLRR-1 and NLRR-2), particularly NLRR-2. Accordingly, it ispresently believed that PRO293 polypeptide disclosed in the presentapplication is a newly identified member of the neuronal leucine richrepeat protein family and possesses ligand-ligand binding activitytypical of the NRLL protein family.

39. Full-Length PRO247 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO247. In particular, Applicants have identified and isolated cDNAencoding a PRO247 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that various portions of the PRO247polypeptide have significant homology with densin. Applicants have alsofound that the DNA encoding the PRO247 polypeptide has significanthomology with a number of other proteins, including KIAA0231.Accordingly, it is presently believed that PRO247 polypeptide disclosedin the present application is a newly identified member of the leucinerich repeat family and possesses ligand binding abilities typical ofthis family.

40. Full-Length PRO302, PRO303, PRO304, PRO307 and PRO343 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO302, PRO303, PRO304, PRO307 and PRO343. In particular, Applicantshave identified and isolated cDNA encoding PRO302, PRO303, PRO304,PRO307 and PRO343 polypeptides, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that various portions of the PRO302, PRO303,PRO304, PRO307 and PRO343 polypeptides have significant homology withvarious protease proteins. Accordingly, it is presently believed thatthe PRO302, PRO303, PRO304, PRO307 and PRO343 polypeptides disclosed inthe present application are newly identified protease proteins.

41. Full-Length PRO328 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO328. In particular, Applicants have identified and isolated cDNAencoding a PRO328 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that various portions of the PRO328polypeptide have significant homology with the human glioblastomaprotein (“GLIP”). Further, Applicants found that various portions of thePRO328 polypeptide have significant homology with the cysteine richsecretory protein (“CRISP”) as identified by BLAST homology[ECCRISP3_(—)1, S68683, and CRS3_HUMAN]. Accordingly, it is presentlybelieved that PRO328 polypeptide disclosed in the present application isa newly identified member of the GLIP or CRISP families and possessestranscriptional regulatory activity typical of the GLIP or CRISPfamilies.

42. Full-Length PRO335, PRO331 and PRO326 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO335, PRO331 or PRO326. In particular, Applicants have identifiedand isolated cDNA encoding a PRO335, PRO331 or PRO326 polypeptide, asdisclosed in further detail in the Examples below. Using BLAST and FastAsequence alignment computer programs, Applicants found that variousportions of the PRO335, PRO331 or PRO326 polypeptide have significanthomology with LIG-1, ALS and in the case of PRO331, additionally,decorin. Accordingly, it is presently believed that the PRO335, PRO331and PRO326 polypeptides disclosed in the present application are newlyidentified members of the leucine rich repeat superfamily, andparticularly, are related to LIG-1 and possess the biological functionsof this family as discussed and referenced herein.

43. Full-Length PRO332 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO332. In particular, Applicants have identified and isolated cDNAencoding PRO332 polypeptides, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that a full-length native sequence PRO332(shown in FIG. 108 and SEQ ID NO:310) has about 30-40% amino acidsequence identity with a series of known proteoglycan sequences,including, for example, fibromodulin and fibromodulin precursorsequences of various species (FMOD_BOVIN, FMOD_CHICK, FMOD_RAT,FMOD_MOUSE, FMOD_HUMAN, P_R36773), osteomodulin sequences(AB000114_(—)1, AB007848_(—)1), decorin sequences (CFU83141_(—)1,OCU03394_(—)1, P R42266, P_R42267, P_R42260, P_R89439), keratan sulfateproteoglycans (BTU48360_(—)1, AF022890_(—)1), corneal proteoglycan(AF022256_(—)1), and bone/cartilage proteoglycans and proteoglycaneprecursors (PGS1_BOVIN, PGS2_MOUSE, PGS2_HUMAN). Accordingly, it ispresently believed that PRO332 disclosed in the present application is anew proteoglycan-type molecule, and may play a role in regulatingextracellular matrix, cartilage, and/or bone function.

44. Full-Length PRO334 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO334. In particular, Applicants have identified and isolated cDNAencoding a PRO334 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that various portions of the PRO334polypeptide have significant homology with fibulin and fibrillin.Accordingly, it is presently believed that PRO334 polypeptide disclosedin the present application is a newly identified member of the epidermalgrowth factor family and possesses properties and activities typical ofthis family.

45. Full-Length PRO346 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO346. In particular, Applicants have identified and isolated cDNAencoding a PRO346 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that a full-length native sequence PRO346(shown in FIG. 112 and SEQ ID NO:320) has 28% amino acid sequenceidentity with carcinoembryonic antigen. Accordingly, it is presentlybelieved that PRO346 disclosed in the present application is a newlyidentified member of the carcinoembryonic protein family and may beexpressed in association with neoplastic tissue disorders.

46. Full-Length PRO268 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO268. In particular, Applicants have identified and isolated cDNAencoding a PRO268 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that portions of the PRO268 polypeptide havesignificant homology with the various protein disulfide isomeraseproteins. Accordingly, it is presently believed that PRO268 polypeptidedisclosed in the present application is a homolog of the proteindisulfide isomerase p5 protein.

47. Full-Length PRO330 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO330. In particular, Applicants have identified and isolated cDNAencoding a PRO330 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that various portions of the PRO330polypeptide have significant homology with the murine prolyl4-hydroxylase alpha-II subunit protein. Accordingly, it is presentlybelieved that PRO330 polypeptide disclosed in the present application isa novel prolyl 4-hydroxylase subunit polypeptide.

48. Full-Length PRO339 and PRO310 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding polypeptides referred to in the present applicationas PRO339 and PRO310. In particular, Applicants have identified andisolated cDNA encoding a PRO339 polypeptide, as disclosed in furtherdetail in the Examples below. Applicants have also identified andisolated cDNA encoding a PRO310 polypeptide, as disclosed in furtherdetail in the Examples below. Using BLAST and FastA sequence alignmentcomputer programs, Applicants found that various portions of the PRO339and PRO310 polypeptides have significant homology with small secretedproteins from C. elegans and are distantly related to fringe. PRO339also shows homology to collagen-like polymers. Sequences which were usedto identify PRO310, designated herein as DNA40533 and DNA42267, alsoshow homology to proteins from C. elegans. Accordingly, it is presentlybelieved that the PRO339 and PRO310 polypeptides disclosed in thepresent application are newly identified member of the family ofproteins involved in development, and which may have regulatoryabilities similar to the capability of fringe to regulate serrate.

49. Full Length PRO244 Polypeptides

The present invention provides newly identified and isolated nucleotidesequences encoding C-type lectins referred to in the present applicationas PRO244. In particular, applicants have identified and isolated cDNAencoding PRO244 polypeptides, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that a full-length native sequence PRO244(shown in FIG. 122 and SEQ ID NO:377) has 43% amino acid sequenceidentity with the hepatic lectin gallus gallus (LECH-CHICK), and 42%amino acid sequence identity with an HIV gp120 binding C-type lectin(A46274). Accordingly, it is presently believed that PRO244 disclosed inthe present application is a newly identified member of the C-lectinsuperfamily and may play a role in immune function, apoptosis, or in thepathogenesis of atherosclerosis. In addition, PRO244 may be useful inidentifying tumor-associated epitopes.

B. PRO Polypeptide Variants

In addition to the full-length native sequence PRO polypeptidesdescribed herein, it is contemplated that PRO variants can be prepared.PRO variants can be prepared by introducing appropriate nucleotidechanges into the PRO DNA, and/or by synthesis of the desired PROpolypeptide. Those skilled in the art will appreciate that amino acidchanges may alter post-translational processes of the PRO, such aschanging the number or position of glycosylation sites or altering themembrane anchoring characteristics.

Variations in the native full-length sequence PRO or in various domainsof the PRO described herein, can be made, for example, using any of thetechniques and guidelines for conservative and non-conservativemutations set forth, for instance, in U.S. Pat. No. 5,364,934.Variations may be a substitution, deletion or insertion of one or morecodons encoding the PRO that results in a change in the amino acidsequence of the PRO as compared with the native sequence PRO. Optionallythe variation is by substitution of at least one amino acid with anyother amino acid in one or more of the domains of the PRO. Guidance indetermining which amino acid residue may be inserted, substituted ordeleted without adversely affecting the desired activity may be found bycomparing the sequence of the PRO with that of homologous known proteinmolecules and minimizing the number of amino acid sequence changes madein regions of high homology. Amino acid substitutions can be the resultof replacing one amino acid with another amino acid having similarstructural and/or chemical properties, such as the replacement of aleucine with a serine, i.e., conservative amino acid replacements.Insertions or deletions may optionally be in the range of about 1 to 5amino acids. The variation allowed may be determined by systematicallymaking insertions, deletions or substitutions of amino acids in thesequence and testing the resulting variants for activity exhibited bythe full-length or mature native sequence.

PRO polypeptide fragments are provided herein. Such fragments may betruncated at the N-terminus or C-terminus, or may lack internalresidues, for example, when compared with a full length native protein.Certain fragments lack amino acid residues that are not essential for adesired biological activity of the PRO polypeptide.

PRO fragments may be prepared by any of a number of conventionaltechniques. Desired peptide fragments may be chemically synthesized. Analternative approach involves generating PRO fragments by enzymaticdigestion, e.g., by treating the protein with an enzyme known to cleaveproteins at sites defined by particular amino acid residues, or bydigesting the DNA with suitable restriction enzymes and isolating thedesired fragment. Yet another suitable technique involves isolating andamplifying a DNA fragment encoding a desired polypeptide fragment, bypolymerase chain reaction (PCR). Oligonucleotides that define thedesired termini of the DNA fragment are employed at the 5′ and 3′primers in the PCR. Preferably, PRO polypeptide fragments share at leastone biological and/or immunological activity with the native PROpolypeptide disclosed herein.

In particular embodiments, conservative substitutions of interest areshown in Table 6 under the heading of preferred substitutions. If suchsubstitutions result in a change in biological activity, then moresubstantial changes, denominated exemplary substitutions in Table 6, oras further described below in reference to amino acid classes, areintroduced and the products screened.

TABLE 6 Original Exemplary Preferred Residue Substitutions SubstitutionsAla (A) val; leu; ile val Arg (R) lys; gln; asn lys Asn (N) gln; his;lys; arg gln Asp (D) glu glu Cys (C) ser ser Gln (Q) asn asn Glu (E) aspasp Gly (G) pro; ala ala His (H) asn; gln; lys; arg arg Ile (I) leu;val; met; ala; phe; leu norleucine Leu (L) norleucine; ile; val; ilemet; ala; phe Lys (K) arg; gln; asn arg Met (M) leu; phe; ile leu Phe(F) leu; val; ile; ala; tyr leu Pro (P) ala ala Ser (S) thr thr Thr (T)ser ser Trp (W) tyr; phe tyr Tyr (Y) trp; phe; thr; ser phe Val (V) ile;leu; met; phe; leu ala; norleucine

Substantial modifications in function or immunological identity of thePRO polypeptide are accomplished by selecting substitutions that differsignificantly in their effect on maintaining (a) the structure of thepolypeptide backbone in the area of the substitution, for example, as asheet or helical conformation, (b) the charge or hydrophobicity of themolecule at the target site, or (c) the bulk of the side chain.Naturally occurring residues are divided into groups based on commonside-chain properties:

(1) hydrophobic: norleucine, met, ala, val, leu, ile;

(2) neutral hydrophilic: cys, ser, thr;

(3) acidic: asp, glu;

(4) basic: asn, gln, his, lys, arg;

(5) residues that influence chain orientation: gly, pro; and

(6) aromatic: trp, tyr, phe.

Non-conservative substitutions will entail exchanging a member of one ofthese classes for another class. Such substituted residues also may beintroduced into the conservative substitution sites or, more preferably,into the remaining (non-conserved) sites.

The variations can be made using methods known in the art such asoligonucleotide-mediated (site-directed) mutagenesis, alanine scanning,and PCR mutagenesis. Site-directed mutagenesis [Carter et al., Nucl.Acids Res., 13:4331 (1986); Zoller et al., Nucl. Acids Res., 10:6487(1987)], cassette mutagenesis [Wells et al., Gene, 34:315 (1985)],restriction selection mutagenesis [Wells et al., Philos. Trans. R. Soc.London SerA, 317:415 (1986)] or other known techniques can be performedon the cloned DNA to produce the PRO variant DNA.

Scanning amino acid analysis can also be employed to identify one ormore amino acids along a contiguous sequence. Among the preferredscanning amino acids are relatively small, neutral amino acids. Suchamino acids include alanine, glycine, serine, and cysteine. Alanine istypically a preferred scanning amino acid among this group because iteliminates the side-chain beyond the beta-carbon and is less likely toalter the main-chain conformation of the variant [Cunningham and Wells,Science, 244: 1081-1085 (1989)]. Alanine is also typically preferredbecause it is the most common amino acid. Further, it is frequentlyfound in both buried and exposed positions [Creighton, The Proteins,(W.H. Freeman & Co., N.Y.); Chothia, J. Mol. Biol., 150:1 (1976)]. Ifalanine substitution does not yield adequate amounts of variant, anisoteric amino acid can be used.

C. Modifications of PRO

Covalent modifications of PRO are included within the scope of thisinvention. One type of covalent modification includes reacting targetedamino acid residues of a PRO polypeptide with an organic derivatizingagent that is capable of reacting with selected side chains or the N- orC- terminal residues of the PRO. Derivatization with bifunctional agentsis useful, for instance, for crosslinking PRO to a water-insolublesupport matrix or surface for use in the method for purifying anti-PROantibodies, and vice-versa. Commonly used crosslinking agents include,e.g., 1,1-bis(diazoacetyl)-2-phenylethane, glutaraldehyde,N-hydroxysuccinimide esters, for example, esters with 4-azidosalicylicacid, homobifunctional imidoesters, including disuccinimidyl esters suchas 3,3′-dithiobis(succinimidylpropionate), bifunctional maleimides suchas bis-N-maleimido-1,8-octane and agents such asmethyl-3-[(p-azidophenyl)dithio]propioimidate.

Other modifications include deamidation of glutaminyl and asparaginylresidues to the corresponding glutamyl and aspartyl residues,respectively, hydroxylation of proline and lysine, phosphorylation ofhydroxyl groups of seryl or threonyl residues, methylation of thea-amino groups of lysine, arginine, and histidine side chains [T. E.Creighton, Proteins: Structure and Molecular Properties, W.H. Freeman &Co., San Francisco, pp. 79-86 (1983)], acetylation of the N-terminalamine, and amidation of any C-terminal carboxyl group.

Another type of covalent modification of the PRO polypeptide includedwithin the scope of this invention comprises altering the nativeglycosylation pattern of the polypeptide. “Altering the nativeglycosylation pattern” is intended for purposes herein to mean deletingone or more carbohydrate moieties found in native sequence PRO (eitherby removing the underlying glycosylation site or by deleting theglycosylation by chemical and/or enzymatic means), and/or adding one ormore glycosylation sites that are not present in the native sequencePRO. In addition, the phrase includes qualitative changes in theglycosylation of the native proteins, involving a change in the natureand proportions of the various carbohydrate moieties present.

Addition of glycosylation sites to the PRO polypeptide may beaccomplished by altering the amino acid sequence. The alteration may bemade, for example, by the addition of, or substitution by, one or moreserine or threonine residues to the native sequence PRO (for O-linkedglycosylation sites). The PRO amino acid sequence may optionally bealtered through changes at the DNA level, particularly by mutating theDNA encoding the PRO polypeptide at preselected bases such that codonsare generated that will translate into the desired amino acids.

Another means of increasing the number of carbohydrate moieties on thePRO polypeptide is by chemical or enzymatic coupling of glycosides tothe polypeptide. Such methods are described in the art, e.g., in WO87/05330 published Sep. 11, 1987, and in Aplin and Wriston, CRC Crit.Rev. Biochem., pp. 259-306 (1981).

Removal of carbohydrate moieties present on the PRO polypeptide may beaccomplished chemically or enzymatically or by mutational substitutionof codons encoding for amino acid residues that serve as targets forglycosylation. Chemical deglycosylation techniques are known in the artand described, for instance, by Hakimuddin, et al., Arch. Biochem.Biophys., 259:52 (1987) and by Edge et al., Anal. Biochem., 118:131(1981). Enzymatic cleavage of carbohydrate moieties on polypeptides canbe achieved by the use of a variety of endo- and exo-glycosidases asdescribed by Thotakura et al., Meth. Enzymol., 138:350 (1987).

Another type of covalent modification of PRO comprises linking the PROpolypeptide to one of a variety of nonproteinaceous polymers, e.g.,polyethylene glycol (PEG), polypropylene glycol, or polyoxyalkylenes, inthe manner set forth in U.S. Pat. Nos. 4,640,835; 4,496,689; 4,301,144;4,670,417; 4,791,192 or 4,179,337.

The PRO of the present invention may also be modified in a way to form achimeric molecule comprising PRO fused to another, heterologouspolypeptide or amino acid sequence.

In one embodiment, such a chimeric molecule comprises a fusion of thePRO with a tag polypeptide which provides an epitope to which ananti-tag antibody can selectively bind. The epitope tag is generallyplaced at the amino- or carboxyl- terminus of the PRO. The presence ofsuch epitope-tagged forms of the PRO can be detected using an antibodyagainst the tag polypeptide. Also, provision of the epitope tag enablesthe PRO to be readily purified by affinity purification using ananti-tag antibody or another type of affinity matrix that binds to theepitope tag. Various tag polypeptides and their respective antibodiesare well known in the art. Examples include poly-histidine (poly-his) orpoly-histidine-glycine (poly-his-gly) tags; the flu HA tag polypeptideand its antibody 12CA5 [Field et al., Mol. Cell. Biol., 8:2159-2165(1988)]; the c-myc tag and the 8F9, 3C7, 6E10, G4, B7 and 9E10antibodies thereto [Evan et al., Molecular and Cellular Biology,5:3610-3616 (1985)]; and the Herpes Simplex virus glycoprotein D (gD)tag and its antibody [Paborsky et al., Protein Engineering, 3(6):547-553(1990)]. Other tag polypeptides include the Flag-peptide [Hopp et al.,BioTechnology, 6:1204-1210 (1988)]; the KT3 epitope peptide [Martin etal., Science, 255:192-194 (1992)]; an α-tubulin epitope peptide [Skinneret al., J. Biol. Chem., 266:15163-15166 (1991)]; and the T7 gene 10protein peptide tag [Lutz-Freyermuth et al., Proc. Natl. Acad. Sci. USA,87:6393-6397 (1990)].

In an alternative embodiment, the chimeric molecule may comprise afusion of the PRO with an inmunoglobulin or a particular region of animmunoglobulin. For a bivalent form of the chimeric molecule (alsoreferred to as an “immunoadhesin”), such a fusion could be to the Fcregion of an IgG molecule. The Ig fusions preferably include thesubstitution of a soluble (transmembrane domain deleted or inactivated)form of a PRO polypeptide in place of at least one variable regionwithin an Ig molecule. In a particularly preferred embodiment, theimmunoglobulin fusion includes the hinge, CH2 and CH3, or the hinge,CH1, CH2 and CH3 regions of an IgG1 molecule. For the production ofimmunoglobulin fusions see also U.S. Pat. No. 5,428,130 issued Jun. 27,1995.

D. Preparation of PRO

The description below relates primarily to production of PRO byculturing cells transformed or transfected with a vector containing PROnucleic acid. It is, of course, contemplated that alternative methods,which are well known in the art, may be employed to prepare PRO. Forinstance, the PRO sequence, or portions thereof, may be produced bydirect peptide synthesis using solid-phase techniques [see, e.g.,Stewart et al., Solid-Phase Peptide Synthesis, W.H. Freeman Co., SanFrancisco, Calif. (1969); Merrifield, J. Am. Chem. Soc., 85:2149-2154(1963)]. In vitro protein synthesis may be performed using manualtechniques or by automation. Automated synthesis may be accomplished,for instance, using an Applied Biosystems Peptide Synthesizer (FosterCity, Calif.) using manufacturer's instructions. Various portions of thePRO may be chemically synthesized separately and combined using chemicalor enzymatic methods to produce the full-length PRO.

1. Isolation of DNA Encoding PRO

DNA encoding PRO may be obtained from a cDNA library prepared fromtissue believed to possess the PRO mRNA and to express it at adetectable level. Accordingly, human PRO DNA can be convenientlyobtained from a cDNA library prepared from human tissue, such asdescribed in the Examples. The PRO-encoding gene may also be obtainedfrom a genomic library or by known synthetic procedures (e.g., automatednucleic acid synthesis).

Libraries can be screened with probes (such as antibodies to the PRO oroligonucleotides of at least about 20-80 bases) designed to identify thegene of interest or the protein encoded by it. Screening the cDNA orgenomic library with the selected probe may be conducted using standardprocedures, such as described in Sambrook et al., Molecular Cloning: ALaboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989).An alternative means to isolate the gene encoding PRO is to use PCRmethodology [Sambrook et al., supra; Dieffenbach et al., PCR Primer: ALaboratory Manual (Cold Spring Harbor Laboratory Press, 1995)].

The Examples below describe techniques for screening a cDNA library. Theoligonucleotide sequences selected as probes should be of sufficientlength and sufficiently unambiguous that false positives are minimized.The oligonucleotide is preferably labeled such that it can be detectedupon hybridization to DNA in the library being screened. Methods oflabeling are well known in the art, and include the use of radiolabelslike ³²P-labeled ATP, biotinylation or enzyme labeling. Hybridizationconditions, including moderate stringency and high stringency, areprovided in Sambrook et al., supra.

Sequences identified in such library screening methods can be comparedand aligned to other known sequences deposited and available in publicdatabases such as GenBank or other private sequence databases. Sequenceidentity (at either the amino acid or nucleotide level) within definedregions of the molecule or across the full-length sequence can bedetermined using methods known in the art and as described herein.

Nucleic acid having protein coding sequence may be obtained by screeningselected cDNA or genomic libraries using the deduced amino acid sequencedisclosed herein for the first time, and, if necessary, usingconventional primer extension procedures as described in Sambrook etal., supra, to detect precursors and processing intermediates of mRNAthat may not have been reverse-transcribed into cDNA.

2. Selection and Transformation of Host Cells

Host cells are transfected or transformed with expression or cloningvectors described herein for PRO production and cultured in conventionalnutrient media modified as appropriate for inducing promoters, selectingtransformants, or amplifying the genes encoding the desired sequences.The culture conditions, such as media, temperature, pH and the like, canbe selected by the skilled artisan without undue experimentation. Ingeneral, principles, protocols, and practical techniques for maximizingthe productivity of cell cultures can be found in Mammalian CellBiotechnology: a Practical Approach, M. Butler, ed. (IRL Press, 1991)and Sambrook et al., supra.

Methods of eukaryotic cell transfection and prokaryotic celltransformation are known to the ordinarily skilled artisan, for example,CaCl₂, CaPO₄, liposome-mediated and electroporation. Depending on thehost cell used, transformation is performed using standard techniquesappropriate to such cells. The calcium treatment employing calciumchloride, as described in Sambrook et al., supra, or electroporation isgenerally used for prokaryotes. Infection with Agrobacterium tumefaciensis used for transformation of certain plant cells, as described by Shawet al., Gene, 23:315 (1983) and WO 89/05859 published Jun. 29, 1989. Formammalian cells without such cell walls, the calcium phosphateprecipitation method of Graham and van der Eb, Virology, 52:456457(1978) can be employed. General aspects of mammalian cell host systemtransfections have been described in U.S. Pat. No. 4,399,216.Transformations into yeast are typically carried out according to themethod of Van Solingen et al., J. Bact., 130:946 (1977) and Hsiao etal., Proc. Natl. Acad. Sci. (USA), 76:3829 (1979). However, othermethods for introducing DNA into cells, such as by nuclearmicroinjection, electroporation, bacterial protoplast fusion with intactcells, or polycations, e.g., polybrene, polyornithine, may also be used.For various techniques for transforming mammalian cells, see Keown etal., Methods in Enzymology, 185:527-537 (1990) and Mansour et al.,Nature, 336:348-352 (1988).

Suitable host cells for cloning or expressing the DNA in the vectorsherein include prokaryote, yeast, or higher eukaryote cells. Suitableprokaryotes include but are not limited to eubacteria, such asGram-negative or Gram-positive organisms, for example,Enterobacteriaceae such as E. coli. Various E. coli strains are publiclyavailable, such as E. coli K12 strain MM294 (ATCC 31,446); E. coli X1776(ATCC 31,537); E. coli strain W3110 (ATCC 27,325) and K5 772 (ATCC53,635). Other suitable prokaryotic host cells includeEnterobacteriaceae such as Escherichia, e.g., E. coli, Enterobacter,Erwinia, Klebsiella, Proteus, Salmonella, e.g., Salmonella typhimurium,Serratia, e.g., Serratia marcescans, and Shigella, as well as Bacillisuch as B. subtilis and B. licheniformis (e.g., B. licheniformis 41Pdisclosed in DD 266,710 published Apr. 12, 1989), Pseudomonas such as P.aeruginosa, and Streptomyces. These examples are illustrative ratherthan limiting. Strain W3110 is one particularly preferred host or parenthost because it is a common host strain for recombinant DNA productfermentations. Preferably, the host cell secretes minimal amounts ofproteolytic enzymes. For example, strain W3110 may be modified to effecta genetic mutation in the genes encoding proteins endogenous to thehost, with examples of such hosts including E. coli W3110 strain 1A2,which has the complete genotype tonA ; E. coli W3110 strain 9E4, whichhas the complete genotype tonA ptr3; E. coli W3110 strain 27C7 (ATCC55,244), which has the complete genotype tonA ptr3phoA E15 (argF-lac)169degP ompT kan^(r) ; E. coli W3110 strain 37D6, which has the completegenotype tonA ptr3 phoA E15 (argF-lac)169 degP ompT rbs7 ilvG kan^(r) ;E. coli W3110 strain 40B4, which is strain 37D6 with a non-kanamycinresistant degP deletion mutation; and an E. coli strain having mutantperiplasmic protease disclosed in U.S. Pat. No. 4,946,783 issued Aug. 7,1990. Alternatively, in vitro methods of cloning, e.g., PCR or othernucleic acid polymerase reactions, are suitable.

In addition to prokaryotes, eukaryotic microbes such as filamentousfungi or yeast are suitable cloning or expression hosts for PRO-encodingvectors. Saccharomyces cerevisiae is a commonly used lower eukaryotichost microorganism. Others include Schizosaccharomyces pombe (Beach andNurse, Nature, 290: 140 [1981]; EP 139,383 published May 2, 1985);Kluyveromyces hosts (U.S. Pat. No. 4,943,529; Fleer et al.,Bio/Technology, 9:968-975 (1991)) such as, e.g., K. lactis (MW98-8C,CBS683, CBS4574; Louvencourt et al., J. Bacteriol., 737 [1983]), K.fragilis (ATCC 12,424), K. bulgaricus (ATCC 16,045), K. wickeramii (ATCC24,178), K. waltii (ATCC 56,500), K. drosophilarum (ATCC 36,906; Van denBerg et al., Bio/Technology, 8:135 (1990)), K. thermotolerans, and K.marxianus; yarrowia (EP 402,226); Pichia pastoris (EP 183,070;Sreekrishna et al., J. Basic Microbiol., 28:265-278 [1988]); Candida;Trichoderma reesia (EP 244,234); Neurospora crassa (Case et al., Proc.Natl. Acad. Sci. USA, 76:5259-5263 [1979]); Schwanniomyces such asSchwanniomyces occidentalis (EP 394,538 published Oct. 31, 1990); andfilamentous fungi such as, e.g., Neurospora, Penicillium, Tolypocladium(WO 91/00357 published Jan. 10, 1991), and Aspergillus hosts such as A.nidulans (Ballance et al., Biochem. Biophys. Res. Commun., 112:284-289[1983]; Tilburn et al., Gene, 26:205-221 [1983]; Yelton et al., Proc.Natl. Acad. Sci. USA, 81: 1470-1474 [1984]) and A. niger (Kelly andHynes, EMBO J., 4:475-479 [1985]). Methylotropic yeasts are suitableherein and include, but are not limited to, yeast capable of growth onmethanol selected from the genera consisting of Hansenula, Candida,Kloeckera, Pichia, Saccharomyces, Torulopsis, and Rhodotorula. A list ofspecific species that are exemplary of this class of yeasts may be foundin C. Anthony, The Biochemistry of Methylotrophs, 269 (1982).

Suitable host cells for the expression of glycosylated PRO are derivedfrom multicellular organisms. Examples of invertebrate cells includeinsect cells such as Drosophila S2 and Spodoptera Sf9, as well as plantcells. Examples of useful mammalian host cell lines include Chinesehamster ovary (CHO) and COS cells. More specific examples include monkeykidney CV1 line transformed by SV40 (COS-7, ATCC CRL 1651); humanembryonic kidney line (293 or 293 cells subcloned for growth insuspension culture, Graham et al., J. Gen Virol., 36:59 (1977)); Chinesehamster ovary cells/-DHFR (CHO, Urlaub and Chasin, Proc. Natl. Acad.Sci. USA, 77:4216 (1980)); mouse sertoli cells (TM4, Mather, Biol.Reprod., 23:243-251 (1980)); human lung cells (W138, ATCC CCL 75); humanliver cells (Hep G2, HB 8065); and mouse mammary tumor (MMT 060562, ATCCCCL51). The selection of the appropriate host cell is deemed to bewithin the skill in the art.

3. Selection and Use of a Replicable Vector

The nucleic acid (e.g., cDNA or genomic DNA) encoding PRO may beinserted into a replicable vector for cloning (amplification of the DNA)or for expression. Various vectors are publicly available. The vectormay, for example, be in the form of a plasmid, cosmid, viral particle,or phage. The appropriate nucleic acid sequence may be inserted into thevector by a variety of procedures. In general, DNA is inserted into anappropriate restriction endonuclease site(s) using techniques known inthe art. Vector components generally include, but are not limited to,one or more of a signal sequence, an origin of replication, one or moremarker genes, an enhancer element, a promoter, and a transcriptiontermination sequence. Construction of suitable vectors containing one ormore of these components employs standard ligation techniques which areknown to the skilled artisan.

The PRO may be produced recombinantly not only directly, but also as afusion polypeptide with a heterologous polypeptide, which may be asignal sequence or other polypeptide having a specific cleavage site atthe N-terminus of the mature protein or polypeptide. In general, thesignal sequence may be a component of the vector, or it may be a part ofthe PRO-encoding DNA that is inserted into the vector. The signalsequence may be a prokaryotic signal sequence selected, for example,from the group of the alkaline phosphatase, penicillinase, lpp, orheat-stable enterotoxin II leaders. For yeast secretion the signalsequence may be, e.g., the yeast invertase leader, alpha factor leader(including Saccharomyces and Kluyveromyces α-factor leaders, the latterdescribed in U.S. Pat. No. 5,010,182), or acid phosphatase leader, theC. albicans glucoamylase leader (EP 362,179 published Apr. 4, 1990), orthe signal described in WO 90/13646 published Nov. 15, 1990. Inmammalian cell expression, mammalian signal sequences may be used todirect secretion of the protein, such as signal sequences from secretedpolypeptides of the same or related species, as well as viral secretoryleaders.

Both expression and cloning vectors contain a nucleic acid sequence thatenables the vector to replicate in one or more selected host cells. Suchsequences are well known for a variety of bacteria, yeast, and viruses.The origin of replication from the plasmid pBR322 is suitable for mostGram-negative bacteria, the 2μ plasmid origin is suitable for yeast, andvarious viral origins (SV40, polyoma, adenovirus, VSV or BPV) are usefulfor cloning vectors in mammalian cells.

Expression and cloning vectors will typically contain a selection gene,also termed a selectable marker. Typical selection genes encode proteinsthat (a) confer resistance to antibiotics or other toxins, e.g.,ampicillin, neomycin, methotrexate, or tetracycline, (b) complementauxotrophic deficiencies, or (c) supply critical nutrients not availablefrom complex media, e.g., the gene encoding D-alanine racemase forBacilli.

An example of suitable selectable markers for mammalian cells are thosethat enable the identification of cells competent to take up thePRO-encoding nucleic acid, such as DHFR or thymidine kinase. Anappropriate host cell when wild-type DHFR is employed is the CHO cellline deficient in DHFR activity, prepared and propagated as described byUrlaub et al., Proc. Natl. Acad. Sci. USA, 77:4216 (1980). A suitableselection gene for use in yeast is the trp1 gene present in the yeastplasmid YRp7 [Stinchcomb et al., Nature, 282:39 (1979); Kingsman et al.,Gene, 7:141 (1979); Tschemper et al., Gene, 10:157 (1980)]. The trp1gene provides a selection marker for a mutant strain of yeast lackingthe ability to grow in tryptophan, for example, ATCC No. 44076 or PEP4-1[Jones, Genetics, 85:12 (1977)].

Expression and cloning vectors usually contain a promoter operablylinked to the PRO-encoding nucleic acid sequence to direct mRNAsynthesis. Promoters recognized by a variety of potential host cells arewell known. Promoters suitable for use with prokaryotic hosts includethe β-lactamase and lactose promoter systems [Chang et al., Nature,275:615 (1978); Goeddel et al., Nature, 281:544 (1979)], alkalinephosphatase, a tryptophan (trp) promoter system [Goeddel, Nucleic AcidsRes., 8:4057 (1980); EP 36,776], and hybrid promoters such as the tacpromoter [deBoer et al., Proc. Natl. Acad. Sci. USA, 80:21-25 (1983)].Promoters for use in bacterial systems also will contain aShine-Dalgarno (S.D.) sequence operably linked to the DNA encoding PRO.

Examples of suitable promoting sequences for use with yeast hostsinclude the promoters for 3-phosphoglycerate kinase [Hitzeman et al., J.Biol. Chem., 255:2073 (1980)] or other glycolytic enzymes [Hess et al.,J. Adv. Enzyme Reg., 7:149 (1968); Holland, Biochemistry, 17:4900(1978)], such as enolase, glyceraldehyde-3-phosphate dehydrogenase,hexokinase, pyruvate decarboxylase, phosphofructokinase,glucose-6-phosphate isomerase, 3-phosphoglycerate mutase, pyruvatekinase, triosephosphate isomerase, phosphoglucose isomerase, andglucokinase.

Other yeast promoters, which are inducible promoters having theadditional advantage of transcription controlled by growth conditions,are the promoter regions for alcohol dehydrogenase 2, isocytochrome C,acid phosphatase, degradative enzymes associated with nitrogenmetabolism, metallothionein, glyceraldehyde-3-phosphate dehydrogenase,and enzymes responsible for maltose and galactose utilization. Suitablevectors and promoters for use in yeast expression are further describedin EP 73,657.

PRO transcription from vectors in mammalian host cells is controlled,for example, by promoters obtained from the genomes of viruses such aspolyoma virus, fowlpox virus (UK 2,211,504 published Jul. 5, 1989),adenovirus (such as Adenovirus 2), bovine papilloma virus, avian sarcomavirus, cytomegalovirus, a retrovirus, hepatitis-B virus and Simian Virus40 (SV40), from heterologous mammalian promoters, e.g., the actinpromoter or an immunoglobulin promoter, and from heat-shock promoters,provided such promoters are compatible with the host cell systems.

Transcription of a DNA encoding the PRO by higher eukaryotes may beincreased by inserting an enhancer sequence into the vector. Enhancersare cis-acting elements of DNA, usually about from 10 to 300 bp, thatact on a promoter to increase its transcription. Many enhancer sequencesare now known from mammalian genes (globin, elastase, albumin,α-fetoprotein, and insulin). Typically, however, one will use anenhancer from a eukaryotic cell virus. Examples include the SV40enhancer on the late side of the replication origin (bp 100-270), thecytomegalovirus early promoter enhancer, the polyoma enhancer on thelate side of the replication origin, and adenovirus enhancers. Theenhancer may be spliced into the vector at a position 5′ or 3′ to thePRO coding sequence, but is preferably located at a site 5′ from thepromoter.

Expression vectors used in eukaryotic host cells (yeast, fungi, insect,plant, animal, human, or nucleated cells from other multicellularorganisms) will also contain sequences necessary for the termination oftranscription and for stabilizing the mRNA. Such sequences are commonlyavailable from the 5′ and, occasionally 3′, untranslated regions ofeukaryotic or viral DNAs or cDNAs. These regions contain nucleotidesegments transcribed as polyadenylated fragments in the untranslatedportion of the mRNA encoding PRO.

Still other methods, vectors, and host cells suitable for adaptation tothe synthesis of PRO in recombinant vertebrate cell culture aredescribed in Gething et al., Nature, 293:620-625 (1981); Mantei et al.,Nature, 281:4046 (1979); EP 117,060; and EP 117,058.

4. Detecting Gene Amplification/Expression

Gene amplification and/or expression may be measured in a sampledirectly, for example, by conventional Southern blotting, Northernblotting to quantitate the transcription of mRNA [Thomas, Proc. Natl.Acad. Sci. USA, 77:5201-5205 (1980)], dot blotting (DNA analysis), or insitu hybridization, using an appropriately labeled probe, based on thesequences provided herein. Alternatively, antibodies may be employedthat can recognize specific duplexes, including DNA duplexes, RNAduplexes, and DNA-RNA hybrid duplexes or DNA-protein duplexes. Theantibodies in turn may be labeled and the assay may be carried out wherethe duplex is bound to a surface, so that upon the formation of duplexon the surface, the presence of antibody bound to the duplex can bedetected.

Gene expression, alternatively, may be measured by immunologicalmethods, such as inununohistochemical staining of cells or tissuesections and assay of cell culture or body fluids, to quantitatedirectly the expression of gene product. Antibodies useful forimmunohistochemical staining and/or assay of sample fluids may be eithermonoclonal or polyclonal, and may be prepared in any mammal.Conveniently, the antibodies may be prepared against a native sequencePRO polypeptide or against a synthetic peptide based on the DNAsequences provided herein or against exogenous sequence fused to PRO DNAand encoding a specific antibody epitope.

5. Purification of Polypeptide

Forms of PRO may be recovered from culture medium or from host celllysates. If membrane-bound, it can be released from the membrane using asuitable detergent solution (e.g. Triton-X 100) or by enzymaticcleavage. Cells employed in expression of PRO can be disrupted byvarious physical or chemical means, such as freeze-thaw cycling,sonication, mechanical disruption, or cell lysing agents.

It may be desired to purify PRO from recombinant cell proteins orpolypeptides. The following procedures are exemplary of suitablepurification procedures: by fractionation on an ion-exchange column;ethanol precipitation; reverse phase HPLC; chromatography on silica oron a cation-exchange resin such as DEAE; chromatofocusing; SDS-PAGE;ammonium sulfate precipitation; gel filtration using, for example,Sephadex G-75; protein A Sepharose columns to remove contaminants suchas IgG; and metal chelating columns to bind epitope-tagged forms of thePRO. Various methods of protein purification may be employed and suchmethods are known in the art and described for example in Deutscher,Methods in Enzymology, 182 (1990); Scopes, Protein Purification:Principles and Practice, Springer-Verlag, New York (1982). Thepurification step(s) selected will depend, for example, on the nature ofthe production process used and the particular PRO produced.

E. Uses for PRO

Nucleotide sequences (or their complement) encoding PRO have variousapplications in the art of molecular biology, including uses ashybridization probes, in chromosome and gene mapping and in thegeneration of anti-sense RNA and DNA. PRO nucleic acid will also beuseful for the preparation of PRO polypeptides by the recombinanttechniques described herein.

The full-length native sequence PRO gene, or portions thereof, may beused as hybridization probes for a cDNA library to isolate thefull-length PRO cDNA or to isolate still other cDNAs (for instance,those encoding naturally-occurring variants of PRO or PRO from otherspecies) which have a desired sequence identity to the native PROsequence disclosed herein. Optionally, the length of the probes will beabout 20 to about 50 bases. The hybridization probes may be derived fromat least partially novel regions of the full length native nucleotidesequence wherein those regions may be determined without undueexperimentation or from genomic sequences including promoters, enhancerelements and introns of native sequence PRO. By way of example, ascreening method will comprise isolating the coding region of the PROgene using the known DNA sequence to synthesize a selected probe ofabout 40 bases. Hybridization probes may be labeled by a variety oflabels, including radionucleotides such as ³²P or 35S, or enzymaticlabels such as alkaline phosphatase coupled to the probe viaavidin/biotin coupling systems. Labeled probes having a sequencecomplementary to that of the PRO gene of the present invention can beused to screen libraries of human cDNA, genomic DNA or mRNA to determinewhich members of such libraries the probe hybridizes to. Hybridizationtechniques are described in further detail in the Examples below.

Any EST sequences disclosed in the present application may similarly beemployed as probes, using the methods disclosed herein.

Other useful fragments of the PRO nucleic acids include antisense orsense oligonucleotides comprising a singe-stranded nucleic acid sequence(either RNA or DNA) capable of binding to target PRO mRNA (sense) or PRODNA (antisense) sequences. Antisense or sense oligonucleotides,according to the present invention, comprise a fragment of the codingregion of PRO DNA. Such a fragment generally comprises at least about 14nucleotides, preferably from about 14 to 30 nucleotides. The ability toderive an antisense or a sense oligonucleotide, based upon a cDNAsequence encoding a given protein is described in, for example, Steinand Cohen (Cancer Res. 48:2659, 1988) and van der Krol et al.(BioTechniques 6:958, 1988).

Binding of antisense or sense oligonucleotides to target nucleic acidsequences results in the formation of duplexes that block transcriptionor translation of the target sequence by one of several means, includingenhanced degradation of the duplexes, premature termination oftranscription or translation, or by other means. The antisenseoligonucleotides thus may be used to block expression of PRO proteins.Antisense or sense oligonucleotides further comprise oligonucleotideshaving modified sugar-phosphodiester backbones (or other sugar linkages,such as those described in WO 91/06629) and wherein such sugar linkagesare resistant to endogenous nucleases. Such oligonucleotides withresistant sugar linkages are stable in vivo (i.e., capable of resistingenzymatic degradation) but retain sequence specificity to be able tobind to target nucleotide sequences.

Other examples of sense or antisense oligonucleotides include thoseoligonucleotides which are covalently linked to organic moieties, suchas those described in WO 90/10048, and other moieties that increasesaffinity of the oligonucleotide for a target nucleic acid sequence, suchas poly-(L-lysine). Further still, intercalating agents, such asellipticine, and alkylating agents or metal complexes may be attached tosense or antisense oligonucleotides to modify binding specificities ofthe antisense or sense oligonucleotide for the target nucleotidesequence.

Antisense or sense oligonucleotides may be introduced into a cellcontaining the target nucleic acid sequence by any gene transfer method,including, for example, CaPO₄-mediated DNA transfection,electroporation, or by using gene transfer vectors such as Epstein-Barrvirus. In a preferred procedure, an antisense or sense oligonucleotideis inserted into a suitable retroviral vector. A cell containing thetarget nucleic acid sequence is contacted with the recombinantretroviral vector, either in vivo or ex vivo. Suitable retroviralvectors include, but are not limited to, those derived from the murineretrovirus M-MuLV, N2 (a retrovirus derived from M-MuLV), or the doublecopy vectors designated DCT5A, DCT5B and DCT5C (see WO 90/13641).

Sense or antisense oligonucleotides also may be introduced into a cellcontaining the target nucleotide sequence by formation of a conjugatewith a ligand binding molecule, as described in WO 91/04753. Suitableligand binding molecules include, but are not limited to, cell surfacereceptors, growth factors, other cytokines, or other ligands that bindto cell surface receptors. Preferably, conjugation of the ligand bindingmolecule does not substantially interfere with the ability of the ligandbinding molecule to bind to its corresponding molecule or receptor, orblock entry of the sense or antisense oligonucleotide or its conjugatedversion into the cell.

Alternatively, a sense or an antisense oligonucleotide may be introducedinto a cell containing the target nucleic acid sequence by formation ofan oligonucleotide-lipid complex, as described in WO 90/10448. The senseor antisense oligonucleotide-lipid complex is preferably dissociatedwithin the cell by an endogenous lipase.

Antisense RNA or DNA molecules are generally at least about 5 bases inlength, about 10 bases in length, about 15 bases in length, about 20bases in length, about 25 bases in length, about 30 bases in length,about 35 bases in length, about 40 bases in length, about 45 bases inlength, about 50 bases in length, about 55 bases in length, about 60bases in length, about 65 bases in length, about 70 bases in length,about 75 bases in length, about 80 bases in length, about 85 bases inlength, about 90 bases in length, about 95 bases in length, about 100bases in length, or more.

The probes may also be employed in PCR techniques to generate a pool ofsequences for identification of closely related PRO coding sequences.

Nucleotide sequences encoding a PRO can also be used to constructhybridization probes for mapping the gene which encodes that PRO and forthe genetic analysis of individuals with genetic disorders. Thenucleotide sequences provided herein may be mapped to a chromosome andspecific regions of a chromosome using known techniques, such as in situhybridization, linkage analysis against known chromosomal markers, andhybridization screening with libraries.

When the coding sequences for PRO encode a protein which binds toanother protein (example, where the PRO is a receptor), the PRO can beused in assays to identify the other proteins or molecules involved inthe binding interaction. By such methods, inhibitors of thereceptor/ligand binding interaction can be identified. Proteins involvedin such binding interactions can also be used to screen for peptide orsmall molecule inhibitors or agonists of the binding interaction. Also,the receptor PRO can be used to isolate correlative ligand(s). Screeningassays can be designed to find lead compounds that mimic the biologicalactivity of a native PRO or a receptor for PRO. Such screening assayswill include assays amenable to high-throughput screening of chemicallibraries, making them particularly suitable for identifying smallmolecule drug candidates. Small molecules contemplated include syntheticorganic or inorganic compounds. The assays can be performed in a varietyof formats, including protein-protein binding assays, biochemicalscreening assays, immunoassays and cell based assays, which are wellcharacterized in the art.

Nucleic acids which encode PRO or its modified forms can also be used togenerate either transgenic animals or “knock out” animals which, inturn, are useful in the development and screening of therapeuticallyuseful reagents. A transgenic animal (e.g., a mouse or rat) is an animalhaving cells that contain a transgene, which transgene was introducedinto the animal or an ancestor of the animal at a prenatal, e.g., anembryonic stage. A transgene is a DNA which is integrated into thegenome of a cell from which a transgenic animal develops. In oneembodiment, cDNA encoding PRO can be used to clone genomic DNA encodingPRO in accordance with established techniques and the genomic sequencesused to generate transgenic animals that contain cells which express DNAencoding PRO. Methods for generating transgenic animals, particularlyanimals such as mice or rats, have become conventional in the art andare described, for example, in U.S. Pat. Nos. 4,736,866 and 4,870,009.Typically, particular cells would be targeted for PRO transgeneincorporation with tissue-specific enhancers. Transgenic animals thatinclude a copy of a transgene encoding PRO introduced into the germ lineof the animal at an embryonic stage can be used to examine the effect ofincreased expression of DNA encoding PRO. Such animals can be used astester animals for reagents thought to confer protection from, forexample, pathological conditions associated with its overexpression. Inaccordance with this facet of the invention, an animal is treated withthe reagent and a reduced incidence of the pathological condition,compared to untreated animals bearing the transgene, would indicate apotential therapeutic intervention for the pathological condition.

Alternatively, non-human homologues of PRO can be used to construct aPRO “knock out” animal which has a defective or altered gene encodingPRO as a result of homologous recombination between the endogenous geneencoding PRO and altered genomic DNA encoding PRO introduced into anembryonic stem cell of the animal. For example, cDNA encoding PRO can beused to clone genomic DNA encoding PRO in accordance with establishedtechniques. A portion of the genomic DNA encoding PRO can be deleted orreplaced with another gene, such as a gene encoding a selectable markerwhich can be used to monitor integration. Typically, several kilobasesof unaltered flanking DNA (both at the 5′ and 3′ ends) are included inthe vector [see e.g., Thomas and Capecchi, Cell, 51:503 (1987) for adescription of homologous recombination vectors]. The vector isintroduced into an embryonic stem cell line (e.g., by electroporation)and cells in which the introduced DNA has homologously recombined withthe endogenous DNA are selected [see e.g., Li et al., Cell 69:915(1992)]. The selected cells are then injected into a blastocyst of ananimal (e.g., a mouse or rat) to form aggregation chimeras [see e.g.,Bradley, in Teratocarcinomas and Embryonic Stem Cells: A PracticalApproach, E. J. Robertson, ed. (IRL, Oxford, 1987), pp. 113-152]. Achimeric embryo can then be implanted into a suitable pseudopregnantfemale foster animal and the embryo brought to term to create a “knockout” animal. Progeny harboring the homologously recombined DNA in theirgerm cells can be identified by standard techniques and used to breedanimals in which all cells of the animal contain the homologouslyrecombined DNA. Knockout animals can be characterized for instance, fortheir ability to defend against certain pathological conditions and fortheir development of pathological conditions due to absence of the PROpolypeptide.

Nucleic acid encoding the PRO polypeptides may also be used in genetherapy. In gene therapy applications, genes are introduced into cellsin order to achieve in vivo synthesis of a therapeutically effectivegenetic product, for example for replacement of a defective gene. “Genetherapy” includes both conventional gene therapy where a lasting effectis achieved by a single treatment, and the administration of genetherapeutic agents, which involves the one time or repeatedadministration of a therapeutically effective DNA or mRNA. AntisenseRNAs and DNAs can be used as therapeutic agents for blocking theexpression of certain genes in vivo. It has already been shown thatshort antisense oligonucleotides can be imported into cells where theyact as inhibitors, despite their low intracellular concentrations causedby their restricted uptake by the cell membrane. (Zamecnik et al., Proc.Natl. Acad. Sci. USA 83:4143-4146 [1986]). The oligonucleotides can bemodified to enhance their uptake, e.g. by substituting their negativelycharged phosphodiester groups by uncharged groups.

There are a variety of techniques available for introducing nucleicacids into viable cells. The techniques vary depending upon whether thenucleic acid is transferred into cultured cells in vitro, or in vivo inthe cells of the intended host. Techniques suitable for the transfer ofnucleic acid into mammalian cells in vitro include the use of liposomes,electroporation, microinjection, cell fusion, DEAE-dextran, the calciumphosphate precipitation method, etc. The currently preferred in vivogene transfer techniques include transfection with viral (typicallyretroviral) vectors and viral coat protein-liposome mediatedtransfection (Dzau et al., Trends in Biotechnology 11, 205-210 [1993]).In some situations it is desirable to provide the nucleic acid sourcewith an agent that targets the target cells, such as an antibodyspecific for a cell surface membrane protein or the target cell, aligand for a receptor on the target cell, etc. Where liposomes areemployed, proteins which bind to a cell surface membrane proteinassociated with endocytosis may be used for targeting and/or tofacilitate uptake, e.g. capsid proteins or fragments thereof tropic fora particular cell type, antibodies for proteins which undergointernalization in cycling, proteins that target intracellularlocalization and enhance intracellular half-life. The technique ofreceptor-mediated endocytosis is described, for example, by Wu et al.,J. Biol. Chem. 262, 4429-4432 (1987); and Wagner et al., Proc. Natl.Acad. Sci. USA 87, 3410-3414 (1990). For review of gene marking and genetherapy protocols see Anderson et al., Science 256, 808-813 (1992).

The PRO polypeptides described herein may also be employed as molecularweight markers for protein electrophoresis purposes and the isolatednucleic acid sequences may be used for recombinantly expressing thosemarkers.

The nucleic acid molecules encoding the PRO polypeptides or fragmentsthereof described herein are useful for chromosome identification. Inthis regard, there exists an ongoing need to identify new chromosomemarkers, since relatively few chromosome marking reagents, based uponactual sequence data are presently available. Each PRO nucleic acidmolecule of the present invention can be used as a chromosome marker.

The PRO polypeptides and nucleic acid molecules of the present inventionmay also be used for tissue typing, wherein the PRO polypeptides of thepresent invention may be differentially expressed in one tissue ascompared to another. PRO nucleic acid molecules will find use forgenerating probes for PCR, Northern analysis, Southern analysis andWestern analysis.

The PRO polypeptides described herein may also be employed astherapeutic agents. The PRO polypeptides of the present invention can beformulated according to known methods to prepare pharmaceutically usefulcompositions, whereby the PRO product hereof is combined in admixturewith a pharmaceutically acceptable carrier vehicle. Therapeuticformulations are prepared for storage by mixing the active ingredienthaving the desired degree of purity with optional physiologicallyacceptable carriers, excipients or stabilizers (Remington'sPharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the formof lyophilized formulations or aqueous solutions. Acceptable carriers,excipients or stabilizers are nontoxic to recipients at the dosages andconcentrations employed, and include buffers such as phosphate, citrateand other organic acids; antioxidants including ascorbic acid; lowmolecular weight (less than about 10 residues) polypeptides; proteins,such as serum albumin, gelatin or immunoglobulins; hydrophilic polymerssuch as polyvinylpyrrolidone, amino acids such as glycine, glutamine,asparagine, arginine or lysine; monosaccharides, disaccharides and othercarbohydrates including glucose, mannose, or dextrins; chelating agentssuch as EDTA; sugar alcohols such as mannitol or sorbitol; salt-formingcounterions such as sodium; and/or nonionic surfactants such as TWEEN™,PLURONICS™ or PEG.

The formulations to be used for in vivo administration must be sterile.This is readily accomplished by filtration through sterile filtrationmembranes, prior to or following lyophilization and reconstitution.

Therapeutic compositions herein generally are placed into a containerhaving a sterile access port, for example, an intravenous solution bagor vial having a stopper pierceable by a hypodermic injection needle.

The route of administration is in accord with known methods, e.g.injection or infusion by intravenous, intraperitoneal, intracerebral,intramuscular, intraocular, intraarterial or intralesional routes,topical administration, or by sustained release systems.

Dosages and desired drug concentrations of pharmaceutical compositionsof the present invention may vary depending on the particular useenvisioned. The determination of the appropriate dosage or route ofadministration is well within the skill of an ordinary physician. Animalexperiments provide reliable guidance for the determination of effectivedoses for human therapy. Interspecies scaling of effective doses can beperformed following the principles laid down by Mordenti, J. andChappell, W. “The use of interspecies scaling in toxicokinetics” InToxicokinetics and New Drug Development, Yacobi et al., Eds., PergamonPress, New York 1989, pp. 42-96.

When in vivo administration of a PRO polypeptide or agonist orantagonist thereof is employed, normal dosage amounts may vary fromabout 10 ng/kg to up to 100 mg/kg of mammal body weight or more per day,preferably about 1 μg/kg/day to 10 mg/kg/day, depending upon the routeof administration. Guidance as to particular dosages and methods ofdelivery is provided in the literature; see, for example, U.S. Pat. Nos.4,657,760; 5,206,344; or 5,225,212. It is anticipated that differentformulations will be effective for different treatment compounds anddifferent disorders, that administration targeting one organ or tissue,for example, may necessitate delivery in a manner different from that toanother organ or tissue.

Where sustained-release administration of a PRO polypeptide is desiredin a formulation with release characteristics suitable for the treatmentof any disease or disorder requiring administration of the PROpolypeptide, microencapsulation of the PRO polypeptide is contemplated.Microencapsulation of recombinant proteins for sustained release hasbeen successfully performed with human growth hormone (rbGH),interferon-(rhIFN-), interleukin-2, and MN rgp120. Johnson et al., Nat.Med., 2:795-799 (1996); Yasuda, Biomed. Ther., 27:1221-1223 (1993); Horaet al., Bio/Technology, 8:755-758 (1990); Cleland, “Design andProduction of Single Immunization Vaccines Using PolylactidePolyglycolide Microsphere Systems,” in Vaccine Design: The Subunit andAdjuvant Approach, Powell and Newman, eds, Plenum Press: New York,1995), pp. 439-462; WO 97/03692, WO 96/40072, WO 96/07399; and U.S. Pat.No. 5,654,010.

The sustained-release formulations of these proteins were developedusing poly-lactic-coglycolic acid (PLGA) polymer due to itsbiocompatibility and wide range of biodegradable properties. Thedegradation products of PLGA, lactic and glycolic acids, can be clearedquickly within the human body. Moreover, the degradability of thispolymer can be adjusted from months to years depending on its molecularweight and composition. Lewis, “Controlled release of bioactive agentsfrom lactide/glycolide polymer,” in: M. Chasin and R. Langer (Eds.),Biodegradable Polymers as Drug Delivery Systems (Marcel Dekker: NewYork, 1990), pp. 1-41.

This invention encompasses methods of screening compounds to identifythose that mimic the PRO polypeptide (agonists) or prevent the effect ofthe PRO polypeptide (antagonists). Screening assays for antagonist drugcandidates are designed to identify compounds that bind or complex withthe PRO polypeptides encoded by the genes identified herein, orotherwise interfere with the interaction of the encoded polypeptideswith other cellular proteins. Such screening assays will include assaysamenable to high-throughput screening of chemical libraries, making themparticularly suitable for identifying small molecule drug candidates.

The assays can be performed in a variety of formats, includingprotein-protein binding assays, biochemical screening assays,immunoassays, and cell-based assays, which are well characterized in theart.

All assays for antagonists are common in that they call for contactingthe drug candidate with a PRO polypeptide encoded by a nucleic acididentified herein under conditions and for a time sufficient to allowthese two components to interact.

In binding assays, the interaction is binding and the complex formed canbe isolated or detected in the reaction mixture. In a particularembodiment, the PRO polypeptide encoded by the gene identified herein orthe drug candidate is immobilized on a solid phase, e.g., on amicrotiter plate, by covalent or non-covalent attachments. Non-covalentattachment generally is accomplished by coating the solid surface with asolution of the PRO polypeptide and drying. Alternatively, animmobilized antibody, e.g., a monoclonal antibody, specific for the PROpolypeptide to be immobilized can be used to anchor it to a solidsurface. The assay is performed by adding the non-immobilized component,which may be labeled by a detectable label, to the immobilizedcomponent, e.g., the coated surface containing the anchored component.When the reaction is complete, the non-reacted components are removed,e.g., by washing, and complexes anchored on the solid surface aredetected. When the originally non-immobilized component carries adetectable label, the detection of label immobilized on the surfaceindicates that complexing occurred. Where the originally non-immobilizedcomponent does not carry a label, complexing can be detected, forexample, by using a labeled antibody specifically binding theimmobilized complex.

If the candidate compound interacts with but does not bind to aparticular PRO polypeptide encoded by a gene identified herein, itsinteraction with that polypeptide can be assayed by methods well knownfor detecting protein-protein interactions. Such assays includetraditional approaches, such as, e.g., cross-linking,co-immunoprecipitation, and co-purification through gradients orchromatographic columns. In addition, protein-protein interactions canbe monitored by using a yeast-based genetic system described by Fieldsand co-workers (Fields and Song, Nature (London), 340:245-246 (1989);Chien et al., Proc. Natl. Acad. Sci. USA, 88:9578-9582 (1991)) asdisclosed by Chevray and Nathans, Proc. Natl. Acad. Sci. USA, 89:5789-5793 (1991). Many transcriptional activators, such as yeast GAL4,consist of two physically discrete modular domains, one acting as theDNA-binding domain, the other one functioning as thetranscription-activation domain. The yeast expression system describedin the foregoing publications (generally referred to as the “two-hybridsystem”) takes advantage of this property, and employs two hybridproteins, one in which the target protein is fused to the DNA-bindingdomain of GAL4, and another, in which candidate activating proteins arefused to the activation domain. The expression of a GAL1-lacZ reportergene under control of a GAL4-activated promoter depends onreconstitution of GAL4 activity via protein-protein interaction.Colonies containing interacting polypeptides are detected with achromogenic substrate for β-galactosidase. A complete kit (MATCHMAKER™)for identifying protein-protein interactions between two specificproteins using the two-hybrid technique is commercially available fromClontech. This system can also be extended to map protein domainsinvolved in specific protein interactions as well as to pinpoint aminoacid residues that are crucial for these interactions.

Compounds that interfere with the interaction of a gene encoding a PROpolypeptide identified herein and other intra- or extracellularcomponents can be tested as follows: usually a reaction mixture isprepared containing the product of the gene and the intra- orextracellular component under conditions and for a time allowing for theinteraction and binding of the two products. To test the ability of acandidate compound to inhibit binding, the reaction is run in theabsence and in the presence of the test compound. In addition, a placebomay be added to a third reaction mixture, to serve as positive control.The binding (complex formation) between the test compound and the intra-or extracellular component present in the mixture is monitored asdescribed hereinabove. The formation of a complex in the controlreaction(s) but not in the reaction mixture containing the test compoundindicates that the test compound interferes with the interaction of thetest compound and its reaction partner.

To assay for antagonists, the PRO polypeptide may be added to a cellalong with the compound to be screened for a particular activity and theability of the compound to inhibit the activity of interest in thepresence of the PRO polypeptide indicates that the compound is anantagonist to the PRO polypeptide. Alternatively, antagonists may bedetected by combining the PRO polypeptide and a potential antagonistwith membrane-bound PRO polypeptide receptors or recombinant receptorsunder appropriate conditions for a competitive inhibition assay. The PROpolypeptide can be labeled, such as by radioactivity, such that thenumber of PRO polypeptide molecules bound to the receptor can be used todetermine the effectiveness of the potential antagonist. The geneencoding the receptor can be identified by numerous methods known tothose of skill in the art, for example, ligand panning and FACS sorting.Coligan et al., Current Protocols in Immun., 1(2): Chapter 5 (1991).Preferably, expression cloning is employed wherein polyadenylated RNA isprepared from a cell responsive to the PRO polypeptide and a cDNAlibrary created from this RNA is divided into pools and used totransfect COS cells or other cells that are not responsive to the PROpolypeptide. Transfected cells that are grown on glass slides areexposed to labeled PRO polypeptide. The PRO polypeptide can be labeledby a variety of means including iodination or inclusion of a recognitionsite for a site-specific protein kinase. Following fixation andincubation, the slides are subjected to autoradiographic analysis.Positive pools are identified and sub-pools are prepared andre-transfected using an interactive sub-pooling and re-screeningprocess, eventually yielding a single clone that encodes the putativereceptor.

As an alternative approach for receptor identification, labeled PROpolypeptide can be photoaffinity-linked with cell membrane or extractpreparations that express the receptor molecule. Cross-linked materialis resolved by PAGE and exposed to X-ray film. The labeled complexcontaining the receptor can be excised, resolved into peptide fragments,and subjected to protein micro-sequencing. The amino acid sequenceobtained from micro-sequencing would be used to design a set ofdegenerate oligonucleotide probes to screen a cDNA library to identifythe gene encoding the putative receptor.

In another assay for antagonists, mammalian cells or a membranepreparation expressing the receptor would be incubated with labeled PROpolypeptide in the presence of the candidate compound. The ability ofthe compound to enhance or block this interaction could then bemeasured.

More specific examples of potential antagonists include anoligonucleotide that binds to the fusions of immunoglobulin with PROpolypeptide, and, in particular, antibodies including, withoutlimitation, poly- and monoclonal antibodies and antibody fragments,single-chain antibodies, anti-idiotypic antibodies, and chimeric orhumanized versions of such antibodies or fragments, as well as humanantibodies and antibody fragments. Alternatively, a potential antagonistmay be a closely related protein, for example, a mutated form of the PROpolypeptide that recognizes the receptor but imparts no effect, therebycompetitively inhibiting the action of the PRO polypeptide.

Another potential PRO polypeptide antagonist is an antisense RNA or DNAconstruct prepared using antisense technology, where, e.g., an antisenseRNA or DNA molecule acts to block directly the translation of mRNA byhybridizing to targeted mRNA and preventing protein translation.Antisense technology can be used to control gene expression throughtriple-helix formation or antisense DNA or RNA, both of which methodsare based on binding of a polynucleotide to DNA or RNA. For example, the5′ coding portion of the polynucleotide sequence, which encodes themature PRO polypeptides herein, is used to design an antisense RNAoligonucleotide of from about 10 to 40 base pairs in length. A DNAoligonucleotide is designed to be complementary to a region of the geneinvolved in transcription (triple helix—see Lee et al., Nucl. AcidsRes., 6:3073 (1979); Cooney et al., Science, 241: 456 (1988); Dervan etal., Science, 251:1360 (1991)), thereby preventing transcription and theproduction of the PRO polypeptide. The antisense RNA oligonucleotidehybridizes to the mRNA in vivo and blocks translation of the mRNAmolecule into the PRO polypeptide (antisense—Okano, Neurochem., 56:560(1991); Oligodeoxynucleotides as Antisense Inhibitors of Gene Expression(CRC Press: Boca Raton, Fla., 1988). The oligonucleotides describedabove can also be delivered to cells such that the antisense RNA or DNAmay be expressed in vivo to inhibit production of the PRO polypeptide.When antisense DNA is used, oligodeoxyribonucleotides derived from thetranslation-initiation site, e.g., between about −10 and +10 positionsof the target gene nucleotide sequence, are preferred.

Potential antagonists include small molecules that bind to the activesite, the receptor binding site, or growth factor or other relevantbinding site of the PRO polypeptide, thereby blocking the normalbiological activity of the PRO polypeptide. Examples of small moleculesinclude, but are not limited to, small peptides or peptide-likemolecules, preferably soluble peptides, and synthetic non-peptidylorganic or inorganic compounds.

Ribozymes are enzymatic RNA molecules capable of catalyzing the specificcleavage of RNA. Ribozymes act by sequence-specific hybridization to thecomplementary target RNA, followed by endonucleolytic cleavage. Specificribozyme cleavage sites within a potential RNA target can be identifiedby known techniques. For further details see, e.g., Rossi, CurrentBiology, 4:469-471 (1994), and PCT publication No. WO 97/33551(published Sep. 18, 1997).

Nucleic acid molecules in triple-helix formation used to inhibittranscription should be single-stranded and composed ofdeoxynucleotides. The base composition of these oligonucleotides isdesigned such that it promotes triple-helix formation via Hoogsteenbase-pairing rules, which generally require sizeable stretches ofpurines or pyrimidines on one strand of a duplex. For further detailssee, e.g., PCT publication No. WO 97/33551, supra.

These small molecules can be identified by any one or more of thescreening assays discussed hereinabove and/or by any other screeningtechniques well known for those skilled in the art.

With regard to the PRO211 and PRO217 polypeptide, therapeuticindications include disorders associated with the preservation andmaintenance of gastrointestinal mucosa and the repair of acute andchronic mucosal lesions (e.g., enterocolitis, Zollinger-Ellisonsyndrome, gastrointestinal ulceration and congenital microvillusatrophy), skin diseases associated with abnormal keratinocytedifferentiation (e.g., psoriasis, epithelial cancers such as lungsquamous cell carcinoma, epidermoid carcinoma of the vulva and gliomas.

Since the PRO232 polypeptide and nucleic acid encoding it possesssequence homology to a cell surface stem cell antigen and its encodingnucleic acid, probes based upon the PRO232 nucleotide sequence may beemployed to identify other novel stem cell surface antigen proteins.Soluble forms of the PRO232 polypeptide may be employed as antagonistsof membrane bound PRO232 activity both in vitro and in vivo. PRO232polypeptides may be employed in screening assays designed to identifyagonists or antagonists of the native PRO232 polypeptide, wherein suchassays may take the form of any conventional cell-type or biochemicalbinding assay. Moreover, the PRO232 polypeptide may serve as a molecularmarker for the tissues in which the polypeptide is specificallyexpressed.

With regard to the PRO187 polypeptides disclosed herein, FGF-8 has beenimplicated in cellular differentiation and embryogenesis, including thepatterning which appears during limb formation. FGF-8 and the PRO187molecules of the invention therefore are likely to have potent effectson cell growth and development. Diseases which relate to cellular growthand differentiation are therefore suitable targets for therapeuticsbased on functionality similar to FGF-8. For example, diseases relatedto growth or survival of nerve cells including Parkinson's disease,Alzheimer's disease, ALS, neuropathies. Additionally, disease related touncontrolled cell growth, e.g., cancer, would also be expectedtherapeutic targets.

With regard to the PRO265 polypeptides disclosed herein, other methodsfor use with PRO265 are described in U.S. Pat. No. 5,654,270 toRuoslahti et al. In particular, PRO265 can be used in comparison withthe fibromodulin disclosed therein to compare its effects on reducingdermal scarring and other properties of the fibromodulin describedtherein including where it is located and with what it binds and doesnot.

The PRO219 polypeptides of the present invention which play a regulatoryrole in the blood coagulation cascade may be employed in vivo fortherapeutic purposes as well as for in vitro purposes. Those of ordinaryskill in the art will well know how to employ PRO219 polypeptides forsuch uses.

The PRO246 polypeptides of the present invention which serve as cellsurface receptors for one or more viruses will find other uses. Forexample, extracellular domains derived from these PRO246 polypeptidesmay be employed therapeutically in vivo for lessening the effects ofviral infection. Those PRO246 polypeptides which serves as tumorspecific antigens may be exploited as therapeutic targets for anti-tumordrugs, and the like. Those of ordinary skill in the art will well knowhow to employ PRO246 polypeptides for such uses.

Assays in which connective growth factor and other growth factors areusually used should be performed with PRO261. An assay to determinewhether TGF beta induces PRO261, indicating a role in cancer isperformed as known in the art. Wound repair and tissue growth assays arealso performed with PRO261. The results are applied accordingly.

PRO228 polypeptides should be used in assays in which EMR1, CD97 andlatrophilin would be used in to determine their relative activities. Theresults can be applied accordingly. For example, a competitive bindingassay with PRO228 and CD97 can be performed with the ligand for CD97,CD55.

Native PRO533 is a 216 amino acid polypeptide of which residues 1-22 arethe signal sequence. Residues 3 to 216 have a Blast score of 509,corresponding to 53% homology to fibroblast growth factor. At thenucleotide level, DNA47412, the EST from which PCR oligos were generatedto isolate the full length DNA49435-1219, has been observed to map to11p15. Sequence homology to the 11p15 locus would indicate that PRO533may have utility in the treatment of Usher Syndrome or Atrophia areata.

As mentioned previously, fibroblast growth factors can act upon cells inboth a mitogenic and non-mitogenic manner. These factors are mitogenicfor a wide variety of normal diploid mesoderm-derived and neuralcrest-derived cells, inducing granulosa cells, adrenal cortical cells,chrondrocytes, myoblasts, corneal and vascular endothelial cells (bovineor human), vascular smooth muscle cells, lens, retina and prostaticepithelial cells, oligodendrocytes, astrocytes, chrondocytes, myoblastsand osteoblasts.

Non-mitogenic actions of fibroblast growth factors include promotion ofcell migration into a wound area (chemotaxis), initiation of new bloodvessel formulation (angiogenesis), modulation of nerve regeneration andsurvival (neurotrophism), modulation of endocrine functions, andstimulation or suppression of specific cellular protein expression,extracellular matrix production and cell survival. Baird, A. & Bohlen,P., Handbook of Exp. Phrmacol. 95(1): 369-418 (1990). These propertiesprovide a basis for using fibroblast growth factors in therapeuticapproaches to accelerate wound healing, nerve repair, collateral bloodvessel formation, and the like. For example, fibroblast growth factors,have been suggested to minimize myocardium damage in heart disease andsurgery (U.S. Pat. No. 4,378,437).

Since the PRO245 polypeptide and nucleic acid encoding it possesssequence homology to a transmembrane protein tyrosine kinase protein andits encoding nucleic acid, probes based upon the PRO245 nucleotidesequence may be employed to identify other novel transmembrane tyrosinekinase proteins. Soluble forms of the PRO245 polypeptide may be employedas antagonists of membrane bound PRO245 activity both in vitro and invivo. PRO245 polypeptides may be employed in screening assays designedto identify agonists or antagonists of the native PRO245 polypeptide,wherein such assays may take the form of any conventional cell-type orbiochemical binding assay. Moreover, the PRO245 polypeptide may serve asa molecular marker for the tissues in which the polypeptide isspecifically expressed.

PRO220, PRO221 and PRO227 all have leucine rich repeats. Additionally,PRO220 and PRO221 have homology to SLIT and leucine rich repeat protein.Therefore, these proteins are useful in assays described in theliterature, supra, wherein the SLIT and leucine rich repeat protein areused. Regarding the SLIT protein, PRO227 can be used in an assay todetermine the affect of PRO227 on neurodegenerative disease.Additionally, PRO227 has homology to human glycoprotein V. In the caseof PRO227, this polypeptide is used in an assay to determine its affecton bleeding, clotting, tissue repair and scarring.

The PRO266 polypeptide can be used in assays to determine if it has arole in neurodegenerative diseases or their reversal.

PRO269 polypeptides and portions thereof which effect the activity ofthrombin may also be useful for in vivo therapeutic purposes, as well asfor various in vitro applications. In addition, PRO269 polypeptides andportions thereof may have therapeutic use as an antithrombotic agentwith reduced risk for hemorrhage as compared with heparin. Peptideshaving homology to thrombomodulin are particularly desirable.

PRO287 polypeptides and portions thereof which effect the activity ofbone morphogenic protein “BMP1”/procollagen C-proteinase (PCP) may alsobe useful for in vivo therapeutic purposes, as well as for various invitro applications. In addition, PRO287 polypeptides and portionsthereof may have therapeutic applications in wound healing and tissuerepair. Peptides having homology to procollagen C-proteinase enhancerprotein and its precursor may also be used to induce bone and/orcartilage formation and are therefore of particular interest to thescientific and medical communities.

Therapeutic indications for PRO214 polypeptides include disordersassociated with the preservation and maintenance of gastrointestinalmucosa and the repair of acute and chronic mucosal lesions (e.g.,enterocolitis, Zollinger-Ellison syndrome, gastrointestinal ulcerationand congenital microvillus atrophy), skin diseases associated withabnormal keratinocyte differentiation (e.g., psoriasis, epithelialcancers such as lung squamous cell carcinoma, epidermoid carcinoma ofthe vulva and gliomas.

Studies on the generation and analysis of mice deficient in members ofthe TGF-superfamily are reported in Matzuk, Trends in Endocrinol. andMetabol., 6: 120-127 (1995).

The PRO317 polypeptide, as well as PRO317-specific antibodies,inhibitors, agonists, receptors, or their analogs, herein are useful intreating PRO317-associated disorders. Hence, for example, they may beemployed in modulating endometrial bleeding angiogenesis, and may alsohave an effect on kidney tissue. Endometrial bleeding can occur ingynecological diseases such as endometrial cancer as abnormal bleeding.Thus, the compositions herein may find use in diagnosing and treatingabnormal bleeding conditions in the endometrium, as by reducing oreliminating the need for a hysterectomy. The molecules herein may alsofind use in angiogenesis applications such as anti-tumor indications forwhich the antibody against vascular endothelial growth factor is used,or, conversely, ischemic indications for which vascular endothelialgrowth factor is employed.

Bioactive compositions comprising PRO317 or agonists or antagoniststhereof may be administered in a suitable therapeutic dose determined byany of several methodologies including clinical studies on mammalianspecies to determine maximal tolerable dose and on normal human subjectsto determine safe dose. Additionally, the bioactive agent may becomplexed with a variety of well established compounds or compositionswhich enhance stability or pharmacological properties such as half-life.It is contemplated that the therapeutic, bioactive composition may bedelivered by intravenous infusion into the bloodstream or any othereffective means which could be used for treating problems of the kidney,uterus, endometrium, blood vessels, or related tissue, e.g., in theheart or genital tract.

Dosages and administration of PRO317, PRO317 agonist, or PRO317antagonist in a pharmaceutical composition may be determined by one ofordinary skill in the art of clinical pharmacology or pharmacokinetics.See, for example, Mordenti and Rescigno, Pharmaceutical Research.9:17-25 (1992); Morenti et al., Pharmaceutical Research, 8:1351-1359(1991); and Mordenti and Chappell, “The use of interspecies scaling intoxicokinetics” in Toxicokinetics and New Drug Development, Yacobi etal. (eds) (Pergamon Press: NY, 1989), pp. 42-96. An effective amount ofPRO317, PRO317 agonist, or PRO317 antagonist to be employedtherapeutically will depend, for example, upon the therapeuticobjectives, the route of administration, and the condition of themammal. Accordingly, it will be necessary for the therapist to titer thedosage and modify the route of administration as required to obtain theoptimal therapeutic effect. A typical daily dosage might range fromabout 10 ng/kg to up to 100 mg/kg of the mammal's body weight or moreper day, preferably about 1 μg/kg/day to 10 mg/kg/day. Typically, theclinician will administer PRO317, PRO317 agonist, or PRO317 antagonist,until a dosage is reached that achieves the desired effect for treatmentof the above mentioned disorders.

PRO317 or an PRO317 agonist or PRO317 antagonist may be administeredalone or in combination with another to achieve the desiredpharmacological effect. PRO317 itself, or agonists or antagonists ofPRO317 can provide different effects when administered therapeutically.Such compounds for treatment will be formulated in a nontoxic, inert,pharmaceutically acceptable aqueous carrier medium preferably at a pH ofabout 5 to 8, more preferably 6 to 8, although the pH may vary accordingto the characteristics of the PRO317, agonist, or antagonist beingformulated and the condition to be treated. Characteristics of thetreatment compounds include solubility of the molecule, half-life, andantigenicity/immunogenicity; these and other characteristics may aid indefining an effective carrier.

PRO317 or PRO317 agonists or PRO317 antagonists may be delivered byknown routes of administration including but not limited to topicalcreams and gels; transmucosal spray and aerosol, transdermal patch andbandage; injectable, intravenous, and lavage formulations; and orallyadministered liquids and pills, particularly formulated to resiststomach acid and enzymes. The particular formulation, exact dosage, androute of administration will be determined by the attending physicianand will vary according to each specific situation.

Such determinations of administration are made by considering multiplevariables such as the condition to be treated, the type of mammal to betreated, the compound to be administered, and the pharmacokineticprofile of the particular treatment compound. Additional factors whichmay be taken into account include disease state (e.g. severity) of thepatient, age, weight, gender, diet, time of administration, drugcombination, reaction sensitivities, and tolerance/response to therapy.Long-acting treatment compound formulations (such as liposomallyencapsulated PRO317 or PEGylated PRO317 or PRO317 polymericmicrospheres, such as polylactic acid-based microspheres) might beadministered every 3 to 4 days, every week, or once every two weeksdepending on half-life and clearance rate of the particular treatmentcompound.

Normal dosage amounts may vary from about 10 ng/kg to up to 100 mg/kg ofmammal body weight or more per day, preferably about 1 μg/kg/day to 10mg/kg/day, depending upon the route of administration. Guidance as toparticular dosages and methods of delivery is provided in theliterature; see, for example, U.S. Pat. Nos. 4,657,760; 5,206,344; or5,225,212. It is anticipated that different formulations will beeffective for different treatment compounds and different disorders,that administration targeting the uterus, for example, may necessitatedelivery in a manner different from that to another organ or tissue,such as cardiac tissue.

Where sustained-release administration of PRO317 is desired in aformulation with release characteristics suitable for the treatment ofany disease or disorder requiring administration of PRO317,microencapsulation of PRO317 is contemplated. Microencapsulation ofrecombinant proteins for sustained release has been successfullyperformed with human growth hormone (rhGH), interferon- (rhIFN- ),interleukin-2, and MN rgp120. Johnson et al., Nat. Med., 2: 795-799(1996); Yasuda. Biomed. Ther., 27: 1221-1223 (1993); Hora et al.,Bio/Technology. 8: 755-758 (1990); Cleland, “Design and Production ofSingle Immunization Vaccines Using Polylactide Polyglycolide MicrosphereSystems,” in Vaccine Design: The Subunit and Adjuvant Approach, Powelland Newman, eds, (Plenum Press: New York, 1995), pp. 439-462; WO97/03692, WO 96/40072, WO 96/07399; and U.S. Pat. No. 5,654,010.

It is contemplated that conditions or diseases of the uterus,endometrial tissue, or other genital tissues or cardiac tissues mayprecipitate damage that is treatable with PRO317 or PRO317 agonist wherePRO317 expression is reduced in the diseased state; or with antibodiesto PRO317 or other PRO317 antagonists where the expression of PRO317 isincreased in the diseased state. These conditions or diseases may bespecifically diagnosed by the probing tests discussed above forphysiologic and pathologic problems which affect the function of theorgan.

The PRO317, PRO317 agonist, or PRO317 antagonist may be administered toa mammal with another biologically active agent, either separately or inthe same formulation to treat a common indication for which they areappropriate. For example, it is contemplated that PRO317 can beadministered together with EBAF-1 for those indications on which theydemonstrate the same qualitative biological effects. Alternatively,where they have opposite effects, EBAF-1 may be administered togetherwith an antagonist to PRO317, such as an anti-PRO317 antibody. Further,PRO317 may be administered together with VEGF for coronary ischemiawhere such indication is warranted, or with an anti-VEGF for cancer aswarranted, or, conversely, an antagonist to PRO317 may be administeredwith VEGF for coronary ischemia or with anti-VEGF to treat cancer aswarranted. These administrations would be in effective amounts fortreating such disorders.

Native PRO301 (SEQ ID NO:1 19) has a Blast score of 246 and 30% homologyat residues 24 to 282 of FIG. 44 with A33_HUMAN, an A33 antigenprecursor. A33 antigen precursor, as explained in the Background is atumor-specific antigen, and as such, is a recognized marker andtherapeutic target for the diagnosis and treatment of colon cancer. Theexpression of tumor-specific antigens is often associated with theprogression of neoplastic tissue disorders. Native PRO301 (SEQ IDNO:119) and A33 HUMAN also show a Blast score of 245 and 30% homology atresidues 21 to 282 of FIG. 44 with A33_HUMAN, the variation dependentupon how spaces are inserted into the compared sequences. Native PRO301(SEQ ID NO:119) also has a Blast score of 165 and 29% homology atresidues 60 to 255 of FIG. 44 with HS46KDA_(—)1, a human coxsackie andadenovirus receptor protein, also known as cell surface protein HCAR.This region of PRO301 also shows a similar Blast score and homology withHSU90716_(—)1. Expression of such proteins is usually associated withviral infection and therapeutics for the prevention of such infectionmay be accordingly conceived. As mentioned in the Background, theexpression of viral receptors is often associated with neoplastictumors.

Therapeutic uses for the PRO234 polypeptides of the invention includestreatments associated with leukocyte homing or the interaction betweenleukocytes and the endothelium during an inflammatory response. Examplesinclude asthma, rheumatoid arthritis, psoriasis and multiple sclerosis.

Since the PRO231 polypeptide and nucleic acid encoding it possesssequence homology to a putative acid phosphatase and its encodingnucleic acid, probes based upon the PRO231 nucleotide sequence may beemployed to identify other novel phosphatase proteins. Soluble forms ofthe PRO231 polypeptide may be employed as antagonists of membrane boundPRO231 activity both in vitro and in vivo. PRO231 polypeptides may beemployed in screening assays designed to identify agonists orantagonists of the native PRO231 polypeptide, wherein such assays maytake the form of any conventional cell-type or biochemical bindingassay. Moreover, the PRO231 polypeptide may serve as a molecular markerfor the tissues in which the polypeptide is specifically expressed.

PRO229 polypeptides can be fused with peptides of interest to determinewhether the fusion peptide has an increased half-life over the peptideof interest. The PRO229 polypeptides can be used accordingly to increasethe half-life of polypeptides of interest. Portions of PRO229 whichcause the increase in half-life are an embodiment of the inventionherein.

PRO238 can be used in assays which measure its ability to reducesubstrates, including oxygen and Aceyl-CoA, and particularly, measurePRO238's ability to produce oxygen free radicals. This is done by usingassays which have been previously described. PRO238 can further be usedto assay for candidates which block, reduce or reverse its reducingabilities. This is done by performing side by side assays wherecandidates are added in one assay having PRO238 and a substrate toreduce, and not added in another assay, being the same but for the lackof the presence of the candidate.

PRO233 polypeptides and portions thereof which have homology toreductase may also be useful for in vivo therapeutic purposes, as wellas for various other applications. The identification of novel reductaseproteins and related molecules may be relevant to a number of humandisorders such as inflammatory disease, organ failure, atherosclerosis,cardiac injury, infertility, birth defects, premature aging, AIDS,cancer, diabetic complications and mutations in general. Given thatoxygen free radicals and antioxidants appear to play important roles ina number of disease processes, the identification of new reductaseproteins and reductase-like molecules is of special importance in thatsuch proteins may serve as potential therapeutics for a variety ofdifferent human disorders. Such polypeptides may also play importantroles in biotechnological and medical research, as well as variousindustrial applications. As a result, there is particular scientific andmedical interest in new molecules, such as PRO233.

The PRO223 polypeptides of the present invention which exhibit serinecarboxypeptidease activity may be employed in vivo for therapeuticpurposes as well as for in vitro purposes. Those of ordinary skill inthe art will well know how to employ PRO223 polypeptides for such uses.

PRO235 polypeptides and portions thereof which may be involved in celladhesion are also useful for in vivo therapeutic purposes, as well asfor various in vitro applications. In addition, PRO235 polypeptides andportions thereof may have therapeutic applications in disease stateswhich involve cell adhesion. Given the physiological importance of celladhesion mechanisms in vivo, efforts are currently being under taken toidentify new, native proteins which are involved in cell adhesion.Therefore, peptides having homology to plexin are of particular interestto the scientific and medical communities.

Because the PRO236 and PRO262 polypeptides disclosed herein arehomologous to various known β-galactosidase proteins, the PRO236 andPRO262 polypeptides disclosed herein will find use in conjugates ofmonoclonal antibodies and the polypeptide for specific killing of tumorcells by generation of active drug from a galactosylated prodrug (e.g.,the generation of 5-fluorouridine from the prodrugβ-D-galactosyl-5-fluorouridine). The PRO236 and PRO262 polypeptidesdisclosed herein may also find various uses both in vivo and in vitro,wherein those uses will be similar or identical to uses for whichβ-galactosidase proteins are now employed. Those of ordinary skill inthe art will well know how to employ PRO236 and PRO262 polypeptides forsuch uses.

PRO239 polypeptides and portions thereof which have homology to densinmay also be useful for in vivo therapeutic purposes, as well as forvarious in vitro applications. In addition, PRO239 polypeptides andportions thereof may have therapeutic applications in disease stateswhich involve synaptic mechanisms, regeneration or cell adhesion. Giventhe physiological importance of synaptic processes, regeneration andcell adhesion mechanisms in vivo, efforts are currently being undertaken to identify new, native proteins which are involved in synapticmachinery and cell adhesion. Therefore, peptides having homology todensin are of particular interest to the scientific and medicalcommunities.

The PRO260 polypeptides described herein can be used in assays todetermine their relation to fucosidase. In particular, the PRO260polypeptides can be used in assays in determining their ability toremove fucose or other sugar residues from proteoglycans. The PRO260polypeptides can be assayed to determine if they have any functional orlocational similarities as fucosidase. The PRO260 polypeptides can thenbe used to regulate the systems in which they are integral.

PRO263 can be used in assays wherein CD44 antigen is generally used todetermine PRO263 activity relative to that of CD44. The results can beused accordingly.

PRO270 polypeptides and portions thereof which effectreduction-oxidation (redox) state may also be useful for in vivotherapeutic purposes, as well as for various in vitro applications. Morespecifically, PRO270 polypeptides may affect the expression of a largevariety of genes thought to be involved in the pathogenesis of AIDS,cancer, atherosclerosis, diabetic complications and in pathologicalconditions involving oxidative stress such as stroke and inflammation.In addition, PRO270 polypeptides and portions thereof may affect theexpression of a genes which have a role in apoptosis. Therefore,peptides having homology to thioredoxin are particularly desirable tothe scientific and medical communities.

PRO272 polypeptides and portions thereof which possess the ability tobind calcium may also have numerous in vivo therapeutic uses, as well asvarious in vitro applications. Therefore, peptides having homology toreticulocalbin are particularly desirable. Those with ordinary skill inthe art will know how to employ PRO272 polypeptides and portions thereoffor such purposes.

PRO294 polypeptides and portions thereof which have homology to collagenmay also be useful for in vivo therapeutic purposes, as well as forvarious other applications. The identification of novel collagens andcollage-like molecules may have relevance to a number of humandisorders. Thus, the identification of new collagens and collage-likemolecules is of special importance in that such proteins may serve aspotential therapeutics for a variety of different human disorders. Suchpolypeptides may also play important roles in biotechnological andmedical research as well as various industrial applications. Given thelarge number of uses for collagen, there is substantial interest inpolypeptides with homology to the collagen molecule.

PRO295 polypeptides and portions thereof which have homology to integrinmay also be useful for in vivo therapeutic purposes, as well as forvarious other applications. The identification of novel integrins andintegrin-like molecules may have relevance to a number of humandisorders such as modulating the binding or activity of cells of theimmune system. Thus, the identification of new integrins andintegrin-like molecules is of special importance in that such proteinsmay serve as potential therapeutics for a variety of different humandisorders. Such polypeptides may also play important roles inbiotechnological and medical research as well as various industrialapplications. As a result, there is particular scientific and medicalinterest in new molecules, such as PRO295.

As the PRO293 polypeptide is clearly a leucine rich repeat polypeptidehomologue, the peptide can be used in all applications that the knownNLRR-1 and NLRR-2 polypeptides are used. The activity can be comparedbetween these peptides and thus applied accordingly.

The PRO247 polypeptides described herein can be used in assays in whichdensin is used to determine the activity of PRO247 relative to densin orthese other proteins. The results can be used accordingly in diagnosticsand/or therapeutic applications with PRO247.

PRO302, PRO303, PRO304, PRO307 and PRO343 polypeptides of the presentinvention which possess protease activity may be employed both in vivofor therapeutic purposes and in vitro. Those of ordinary skill in theart will well know how to employ the PRO302, PRO303, PRO304, PRO307 andPRO343 polypeptides of the present invention for such purposes.

PRO328 polypeptides and portions thereof which have homology to GLIP andCRISP may also be useful for in vivo therapeutic purposes, as well asfor various other applications. The identification of novel GLIP andCRISP-like molecules may have relevance to a number of human disorderswhich involve transcriptional regulation or are over expressed in humantumors. Thus, the identification of new GLIP and CRISP-like molecules isof special importance in that such proteins may serve as potentialtherapeutics for a variety of different human disorders. Suchpolypeptides may also play important roles in biotechnological andmedical research as well as in various industrial applications. As aresult, there is particular scientific and medical interest in newmolecules, such as PRO328.

Uses for PRO335, PRO331 or PRO326 including uses in competitive assayswith LIG-1, ALS and decorin to determine their relative activities. Theresults can be used accordingly. PRO335, PRO331 or PRO326 can also beused in assays where LIG-1 would be used to determine if the sameeffects are incurred.

PRO332 contains GAG repeat (GKEK) at amino acid positions 625-628 inFIG. 108 (SEQ ID NO:310). Slippage in such repeats can be associatedwith human disease. Accordingly, PRO332 can use useful for the treatmentof such disease conditions by gene therapy, i.e. by introduction of agene containing the correct GKEK sequence motif.

Other uses of PRO334 include use in assays in which fibrillin or fibulinwould be used to determine the relative activity of PRO334 to fibrillinor fibulin. In particular, PRO334 can be used in assays which requirethe mechanisms imparted by epidermal growth factor repeats.

Native PRO346 (SEQ ID NO:320) has a Blast score of 230, corresponding to27% homology between amino acid residues 21 to 343 with residues 35 to1040 CGM6_HUMAN, a carcinoembryonic antigen cgm6 precursor. Thishomology region includes nearly all but 2 N-terminal extracellulardomain residues, including an immunoglobulin superfamily homology atresidues 148 to 339 of PRO346 in addition to several transmembraneresidues (340-343). Carcinoembryonic antigen precursor, as explained inthe Background is a tumor-specific antigen, and as such, is a recognizedmarker and therapeutic target for the diagnosis and treatment of coloncancer. The expression of tumor-specific antigens is often associatedwith the progression of neoplastic tissue disorders. Native PRO346 (SEQID NO:320) and P_WO6874, a human carcinoembryonic antigen CEA-d have aBlast score of 224 and homology of 28% between residues 2 to 343 and 67to 342, respectively. This homology includes the entire extracellulardomain residues of native PRO346, minus the initiator methionine(residues 2 to 18) as well as several transmembrane residues (340-343).

PRO268 polypeptides which have protein disulfide isomerase activity willbe useful for many applications where protein disulfide isomeraseactivity is desirable including, for example, for use in promotingproper disulfide bond formation in recombinantly produced proteins so asto increase the yield of correctly folded protein. Those of ordinaryskill in the art will readily know how to employ such PRO268polypeptides for such purposes.

PRO330 polypeptides of the present invention which possess biologicalactivity related to that of the prolyl 4-hydroxylase alpha subunitprotein may be employed both in vivo for therapeutic purposes and invitro. Those of ordinary skill in the art will well know how to employthe PRO330 polypeptides of the present invention for such purposes.

Uses of the herein disclosed molecules may also be based upon thepositive functional assay hits disclosed and described below.

F. Anti-PRO Antibodies

The present invention further provides anti-PRO antibodies. Exemplaryantibodies include polyclonal, monoclonal, humanized, bispecific, andheteroconjugate antibodies.

1. Polyclonal Antibodies

The anti-PRO antibodies may comprise polyclonal antibodies. Methods ofpreparing polyclonal antibodies are known to the skilled artisan.Polyclonal antibodies can be raised in a mammal, for example, by one ormore injections of an immunizing agent and, if desired, an adjuvant.Typically, the immunizing agent and/or adjuvant will be injected in themammal by multiple subcutaneous or intraperitoneal injections. Theimmunizing agent may include the PRO polypeptide or a fusion proteinthereof. It may be useful to conjugate the immunizing agent to a proteinknown to be immunogenic in the mammal being immunized. Examples of suchimmunogenic proteins include but are not limited to keyhole limpethemocyanin, serum albumin, bovine thyroglobulin, and soybean trypsininhibitor. Examples of adjuvants which may be employed include Freund'scomplete adjuvant and MPL-TDM adjuvant (monophosphoryl Lipid A,synthetic trehalose dicorynomycolate). The immunization protocol may beselected by one skilled in the art without undue experimentation.

2. Monoclonal Antibodies

The anti-PRO antibodies may, alternatively, be monoclonal antibodies.Monoclonal antibodies may be prepared using hybridoma methods, such asthose described by Kohler and Milstein, Nature 256:495 (1975). In ahybridoma method, a mouse, hamster, or other appropriate host animal, istypically immunized with an immunizing agent to elicit lymphocytes thatproduce or are capable of producing antibodies that will specificallybind to the immunizing agent. Alternatively, the lymphocytes may beimmunized in vitro.

The immunizing agent will typically include the PRO polypeptide or afusion protein thereof. Generally, either peripheral blood lymphocytes(“PBLs”) are used if cells of human origin are desired, or spleen cellsor lymph node cells are used if non-human mammalian sources are desired.The lymphocytes are then fused with an immortalized cell line using asuitable fusing agent, such as polyethylene glycol, to form a hybridomacell [Goding, Monoclonal Antibodies: Principles and Practice, AcademicPress, (1986) pp. 59-103]. Immortalized cell lines are usuallytransformed mammalian cells, particularly myeloma cells of rodent,bovine and human origin. Usually, rat or mouse myeloma cell lines areemployed. The hybridoma cells may be cultured in a suitable culturemedium that preferably contains one or more substances that inhibit thegrowth or survival of the unfused, immortalized cells. For example, ifthe parental cells lack the enzyme hypoxanthine guanine phosphoribosyltransferase (HGPRT or HPRT), the culture medium for the hybridomastypically will include hypoxanthine, aminopterin, and thymidine (“HATmedium”), which substances prevent the growth of HGPRT-deficient cells.

Preferred immortalized cell lines are those that fuse efficiently,support stable high level expression of antibody by the selectedantibody-producing cells, and are sensitive to a medium such as HATmedium. More preferred immortalized cell lines are murine myeloma lines,which can be obtained, for instance, from the Salk Institute CellDistribution Center, San Diego, Calif. and the American Type CultureCollection, Manassas, Va. Human myeloma and mouse-human heteromyelomacell lines also have been described for the production of humanmonoclonal antibodies [Kozbor, J. Immunol., 133:3001 (1984); Brodcur etal., Monoclonal Antibody Production Techniques and Applications, MarcelDekker, Inc., New York, (1987) pp. 51-63].

The culture medium in which the hybridoma cells are cultured can then beassayed for the presence of monoclonal antibodies directed against PRO.Preferably, the binding specificity of monoclonal antibodies produced bythe hybridoma cells is determined by immunoprecipitation or by an invitro binding assay, such as radioimmunoassay (RIA) or enzyme-linkedimmunoabsorbent assay (ELISA). Such techniques and assays are known inthe art. The binding affinity of the monoclonal antibody can, forexample, be determined by the Scatchard analysis of Munson and Pollard,Anal. Biochem. 107:220 (1980).

After the desired hybridoma cells are identified, the clones may besubcloned by limiting dilution procedures and grown by standard methods[Goding, supra]. Suitable culture media for this purpose include, forexample, Dulbecco's Modified Eagle's Medium and RPMI-1640 medium.Alternatively, the hybridoma cells may be grown in vivo as ascites in amammal.

The monoclonal antibodies secreted by the subclones may be isolated orpurified from the culture medium or ascites fluid by conventionalimmunoglobulin purification procedures such as, for example, proteinA-Sepharose, hydroxylapatite chromatography, gel electrophoresis,dialysis, or affinity chromatography.

The monoclonal antibodies may also be made by recombinant DNA methods,such as those described in U.S. Pat. No. 4,816,567. DNA encoding themonoclonal antibodies of the invention can be readily isolated andsequenced using conventional procedures (e.g., by using oligonucleotideprobes that are capable of binding specifically to genes encoding theheavy and light chains of murine antibodies). The hybridoma cells of theinvention serve as a preferred source of such DNA. Once isolated, theDNA may be placed into expression vectors, which are then transfectedinto host cells such as simian COS cells, Chinese hamster ovary (CHO)cells, or myeloma cells that do not otherwise produce immunoglobulinprotein, to obtain the synthesis of monoclonal antibodies in therecombinant host cells. The DNA also may be modified, for example, bysubstituting the coding sequence for human heavy and light chainconstant domains in place of the homologous murine sequences [U.S. Pat.No. 4,816,567; Morrison et al., supra or by covalently joining to theimmunoglobulin coding sequence all or part of the coding sequence for anon-immunoglobulin polypeptide. Such a non-immunoglobulin polypeptidecan be substituted for the constant domains of an antibody of theinvention, or can be substituted for the variable domains of oneantigen-combining site of an antibody of the invention to create achimeric bivalent antibody.

The antibodies may be monovalent antibodies. Methods for preparingmonovalent antibodies are well known in the art. For example, one methodinvolves recombinant expression of immunoglobulin light chain andmodified heavy chain. The heavy chain is truncated generally at anypoint in the Fc region so as to prevent heavy chain crosslinking.Alternatively, the relevant cysteine residues are substituted withanother amino acid residue or are deleted so as to prevent crosslinking.

In vitro methods are also suitable for preparing monovalent antibodies.Digestion of antibodies to produce fragments thereof, particularly, Fabfragments, can be accomplished using routine techniques known in theart.

3. Human and Humanized Antibodies

The anti-PRO antibodies of the invention may further comprise humanizedantibodies or human antibodies. Humanized forms of non-human (e.g.,murine) antibodies are chimeric immunoglobulins, immunoglobulin chainsor fragments thereof (such as Fv, Fab, Fab′, F(ab′)₂ or otherantigen-binding subsequences of antibodies) which contain minimalsequence derived from non-human immunoglobulin. Humanized antibodiesinclude human immunoglobulins (recipient antibody) in which residuesfrom a complementary determining region (CDR) of the recipient arereplaced by residues from a CDR of a non-human species (donor antibody)such as mouse, rat or rabbit having the desired specificity, affinityand capacity. In some instances, Fv framework residues of the humanimmunoglobulin are replaced by corresponding non-human residues.Humanized antibodies may also comprise residues which are found neitherin the recipient antibody nor in the imported CDR or frameworksequences. In general, the humanized antibody will comprisesubstantially all of at least one, and typically two, variable domains,in which all or substantially all of the CDR regions correspond to thoseof a non-human immunoglobulin and all or substantially all of the FRregions are those of a human immunoglobulin consensus sequence. Thehumanized antibody optimally also will comprise at least a portion of animmunoglobulin constant region (Fc), typically that of a humanimmunoglobulin [Jones et al., Nature, 321:522-525 (1986); Riechmann etal., Nature, 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol.,2:593-596 (1992)].

Methods for humanizing non-human antibodies are well known in the art.Generally, a humanized antibody has one or more amino acid residuesintroduced into it from a source which is non-human. These non-humanamino acid residues are often referred to as “import” residues, whichare typically taken from an “import” variable domain. Humanization canbe essentially performed following the method of Winter and co-workers[Jones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature,332:323-327 (1988); Verhoeyen et al., Science, 239:1534-1536 (1988)], bysubstituting rodent CDRs or CDR sequences for the correspondingsequences of a human antibody. Accordingly, such “humanized” antibodiesare chimeric antibodies (U.S. Pat. No. 4,816,567), wherein substantiallyless than an intact human variable domain has been substituted by thecorresponding sequence from a non-human species. In practice, humanizedantibodies are typically human antibodies in which some CDR residues andpossibly some FR residues are substituted by residues from analogoussites in rodent antibodies.

Human antibodies can also be produced using various techniques known inthe art, including phage display libraries [Hoogenboom and Winter, J.Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581(1991)]. The techniques of Cole et al. and Boerner et al. are alsoavailable for the preparation of human monoclonal antibodies (Cole etal., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77(1985) and Boerner et al., J. Immunol., 147(1):86-95 (1991)1. Similarly,human antibodies can be made by introducing of human immunoglobulin lociinto transgenic animals, e.g., mice in which the endogenousimmunoglobulin genes have been partially or completely inactivated. Uponchallenge, human antibody production is observed, which closelyresembles that seen in humans in all respects, including generearrangement, assembly, and antibody repertoire. This approach isdescribed, for example, in U.S. Pat. Nos. 5,545,807; 5,545,806;5,569,825; 5,625,126; 5,633,425; 5,661,016, and in the followingscientific publications: Marks et al., Bio/Technology 10, 779-783(1992); Lonberg et al., Nature 368 856-859 (1994); Morrison, Nature 368,812-13 (1994); Fishwild et al., Nature Biotechnology 14, 845-51 (1996);Neuberger, Nature Biotechnology 14, 826 (1996); Lonberg and Huszar,Intern. Rev. Immunol. 13 65-93 (1995).

4. Bispecific Antibodies

Bispecific antibodies are monoclonal, preferably human or humanized,antibodies that have binding specificities for at least two differentantigens. In the present case, one of the binding specificities is forthe PRO, the other one is for any other antigen, and preferably for acell-surface protein or receptor or receptor subunit.

Methods for making bispecific antibodies are known in the art.Traditionally, the recombinant production of bispecific antibodies isbased on the co-expression of two immunoglobulin heavy-chain/light-chainpairs, where the two heavy chains have different specificities [Milsteinand Cuello, Nature, 305:537-539 (1983)]. Because of the randomassortment of immunoglobulin heavy and light chains, these hybridomas(quadromas) produce a potential mixture of ten different antibodymolecules, of which only one has the correct bispecific structure. Thepurification of the correct molecule is usually accomplished by affinitychromatography steps. Similar procedures are disclosed in WO 93/08829,published May 13, 1993, and in Traunecker et al., EMBO J., 10:3655-3659(1991).

Antibody variable domains with the desired binding specificities(antibody-antigen combining sites) can be fused to immunoglobulinconstant domain sequences. The fusion preferably is with animmunoglobulin heavy-chain constant domain, comprising at least part ofthe hinge, CH2, and CH3 regions. It is preferred to have the firstheavy-chain constant region (CH1) containing the site necessary forlight-chain binding present in at least one of the fusions. DNAsencoding the immunoglobulin heavy-chain fusions and, if desired, theimmunoglobulin light chain, are inserted into separate expressionvectors, and are co-transfected into a suitable host organism. Forfurther details of generating bispecific antibodies see, for example,Suresh et al., Methods in Enzymology, 121:210 (1986).

According to another approach described in WO 96/27011, the interfacebetween a pair of antibody molecules can be engineered to maximize thepercentage of heterodimers which are recovered from recombinant cellculture. The preferred interface comprises at least a part of the CH3region of an antibody constant domain. In this method, one or more smallamino acid side chains from the interface of the first antibody moleculeare replaced with larger side chains (e.g. tyrosine or tryptophan).Compensatory “cavities” of identical or similar size to the large sidechain(s) are created on the interface of the second antibody molecule byreplacing large amino acid side chains with smaller ones (e.g. alanineor threonine). This provides a mechanism for increasing the yield of theheterodimer over other unwanted end-products such as homodimers.

Bispecific antibodies can be prepared as full length antibodies orantibody fragments (e.g. F(ab′)₂ bispecific antibodies). Techniques forgenerating bispecific antibodies from antibody fragments have beendescribed in the literature. For example, bispecific antibodies can beprepared can be prepared using chemical linkage. Brennan et al., Science229:81 (1985) describe a procedure wherein intact antibodies areproteolytically cleaved to generate F(ab′)₂ fragments. These fragmentsare reduced in the presence of the dithiol complexing agent sodiumarsenite to stabilize vicinal dithiols and prevent intermoleculardisulfide formation. The Fab′ fragments generated are then converted tothionitrobenzoate (TNB) derivatives. One of the Fab′-TNB derivatives isthen reconverted to the Fab′-thiol by reduction with mercaptoethylamineand is mixed with an equimolar amount of the other Fab′-TNB derivativeto form the bispecific antibody. The bispecific antibodies produced canbe used as agents for the selective immobilization of enzymes.

Fab′ fragments may be directly recovered from E. coli and chemicallycoupled to form bispecific antibodies. Shalaby et al., J. Exp. Med.175:217-225 (1992) describe the production of a fully humanizedbispecific antibody F(ab′)₂ molecule. Each Fab′ fragment was separatelysecreted from E. coli and subjected to directed chemical coupling invitro to form the bispecific antibody. The bispecific antibody thusformed was able to bind to cells overexpressing the ErbB2 receptor andnormal human T cells, as well as trigger the lytic activity of humancytotoxic lymphocytes against human breast tumor targets.

Various technique for making and isolating bispecific antibody fragmentsdirectly from recombinant cell culture have also been described. Forexample, bispecific antibodies have been produced using leucine zippers.Kostelny et al., J. Immunol. 148(5):1547-1553 (1992). The leucine zipperpeptides from the Fos and Jun proteins were linked to the Fab′ portionsof two different antibodies by gene fusion. The antibody homodimers werereduced at the hinge region to form monomers and then re-oxidized toform the antibody heterodimers. This method can also be utilized for theproduction of antibody homodimers. The “diabody” technology described byHollinger et al., Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993) hasprovided an alternative mechanism for making bispecific antibodyfragments. The fragments comprise a heavy-chain variable domain (V_(H))connected to a light-chain variable domain (V_(L)) by a linker which istoo short to allow pairing between the two domains on the same chain.Accordingly, the V_(H) and V_(L) domains of one fragment are forced topair with the complementary V_(L) and V_(H) domains of another fragment,thereby forming two antigen-binding sites. Another strategy for makingbispecific antibody fragments by the use of single-chain Fv (sFv) dimershas also been reported. See, Gruber et al., J. Immunol. 152:5368 (1994).Antibodies with more than two valencies are contemplated. For example,trispecific antibodies can be prepared. Tutt et al., J. Immunol. 147:60(1991).

Exemplary bispecific antibodies may bind to two different epitopes on agiven PRO polypeptide herein. Alternatively, an anti-PRO polypeptide armmay be combined with an arm which binds to a triggering molecule on aleukocyte such as a T-cell receptor molecule (e.g. CD2, CD3, CD28, orB7), or Fc receptors for IgG (FcγR), such as FcγRI (CD64), FcγRII (CD32)and FcγRIII (CD16) so as to focus cellular defense mechanisms to thecell expressing the particular PRO polypeptide. Bispecific antibodiesmay also be used to localize cytotoxic agents to cells which express aparticular PRO polypeptide. These antibodies possess a PRO-binding armand an arm which binds a cytotoxic agent or a radionuclide chelator,such as EOTUBE, DPTA, DOTA, or TETA. Another bispecific antibody ofinterest binds the PRO polypeptide and further binds tissue factor (TF).

5. Heteroconjugate Antibodies

Heteroconjugate antibodies are also within the scope of the presentinvention. Heteroconjugate antibodies are composed of two covalentlyjoined antibodies. Such antibodies have, for example, been proposed totarget immune system cells to unwanted cells [U.S. Pat. No. 4,676,980],and for treatment of HIV infection [WO 91100360; WO 92/200373; EP03089]. It is contemplated that the antibodies may be prepared in vitrousing known methods in synthetic protein chemistry, including thoseinvolving crosslinking agents. For example, immunotoxins may beconstructed using a disulfide exchange reaction or by forming athioether bond. Examples of suitable reagents for this purpose includeiminothiolate and methyl-4-mercaptobutyrimidate and those disclosed, forexample, in U.S. Pat. No. 4,676,980.

6. Effector Function Engineering

It may be desirable to modify the antibody of the invention with respectto effector function, so as to enhance, e.g., the effectiveness of theantibody in treating cancer. For example, cysteine residue(s) may beintroduced into the Fc region, thereby allowing interchain disulfidebond formation in this region. The homodimeric antibody thus generatedmay have improved internalization capability and/or increasedcomplement-mediated cell killing and antibody-dependent cellularcytotoxicity (ADCC). See Caron et al., J. Exp Med., 176: 1191-1195(1992) and Shopes, J. Immunol., 148: 2918-2922 (1992). Homodimericantibodies with enhanced anti-tumor activity may also be prepared usingheterobifunctional cross-linkers as described in Wolff et al. CancerResearch, 53: 2560-2565 (1993). Alternatively, an antibody can beengineered that has dual Fc regions and may thereby have enhancedcomplement lysis and ADCC capabilities. See Stevenson et al.,Anti-Cancer Drug Design. 3: 219-230 (1989).

7. Immunoconjugates

The invention also pertains to immunoconjugates comprising an antibodyconjugated to a cytotoxic agent such as a chemotherapeutic agent, toxin(e.g., an enzymatically active toxin of bacterial, fungal, plant, oranimal origin, or fragments thereof), or a radioactive isotope (i.e., aradioconjugate).

Chemotherapeutic agents useful in the generation of suchimmunoconjugates have been described above. Enzymatically active toxinsand fragments thereof that can be used include diphtheria A chain,nonbinding active fragments of diphtheria toxin, exotoxin A chain (fromPseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain,alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolacaamericana proteins (PAPI, PAPII, and PAP-S), momordica charantiainhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin,mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes. Avariety of radionuclides are available for the production ofradioconjugated antibodies. Examples include ²¹²Bi, ¹³¹I, ¹³¹In, ⁹⁰Y,and ¹⁸⁶Re.

Conjugates of the antibody and cytotoxic agent are made using a varietyof bifunctional protein-coupling agents such asN-succinimidyl-3-(2-pyridyldithiol) propionate (SPDP), iminothiolane(IT), bifunctional derivatives of imidoesters (such as dimethyladipimidate HCL), active esters (such as disuccinimidyl suberate),aldehydes (such as glutareldehyde), bis-azido compounds (such as bis(p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such asbis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such astolyene 2,6-diisocyanate), and bis-active fluorine compounds (such as1,5-difluoro-2,4-dinitrobenzene). For example, a ricin immunotoxin canbe prepared as described in Vitetta et al., Science, 238: 1098 (1987).Carbon-14-labeled 1-isothiocyanatobenzyl-3-methyldiethylenetriaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent forconjugation of radionucleotide to the antibody. See WO94/11026.

In another embodiment, the antibody may be conjugated to a “receptor”(such streptavidin) for utilization in tumor pretargeting wherein theantibody-receptor conjugate is administered to the patient, followed byremoval of unbound conjugate from the circulation using a clearing agentand then administration of a “ligand” (e.g., avidin) that is conjugatedto a cytotoxic agent (e.g., a radionucleotide).

8. Immunoliposomes

The antibodies disclosed herein may also be formulated asimmunoliposomes. Liposomes containing the antibody are prepared bymethods known in the art, such as described in Epstein et al., Proc.Natl. Acad. Sci. USA, 82: 3688 (1985); Hwang et al., Proc. Natl Acad.Sci. USA, 77: 4030 (1980); and U.S. Pat. Nos. 4,485,045 and 4,544,545.Liposomes with enhanced circulation time are disclosed in U.S. Pat. No.5,013,556.

Particularly useful liposomes can be generated by the reverse-phaseevaporation method with a lipid composition comprisingphosphatidylcholine, cholesterol, and PEG-derivatizedphosphatidylethanolamine (PEG-PE). Liposomes are extruded throughfilters of defined pore size to yield liposomes with the desireddiameter. Fab′ fragments of the antibody of the present invention can beconjugated to the liposomes as described in Martin et al., J. Biol.Chem., 257: 286-288 (1982) via a disulfide-interchange reaction. Achemotherapeutic agent (such as Doxorubicin) is optionally containedwithin the liposome. See Gabizon et al., J. National Cancer Inst.,81(19): 1484 (1989).

9. Pharmaceutical Compositions of Antibodies

Antibodies specifically binding a PRO polypeptide identified herein, aswell as other molecules identified by the screening assays disclosedhereinbefore, can be administered for the treatment of various disordersin the form of pharmaceutical compositions.

If the PRO polypeptide is intracellular and whole antibodies are used asinhibitors, internalizing antibodies are preferred. However,lipofections or liposomes can also be used to deliver the antibody, oran antibody fragment, into cells. Where antibody fragments are used, thesmallest inhibitory fragment that specifically binds to the bindingdomain of the target protein is preferred. For example, based upon thevariable-region sequences of an antibody, peptide molecules can bedesigned that retain the ability to bind the target protein sequence.Such peptides can be synthesized chemically and/or produced byrecombinant DNA technology. See, e.g., Marasco et al., Proc. Natl. Acad.Sci. USA, 90: 7889-7893 (1993). The formulation herein may also containmore than one active compound as necessary for the particular indicationbeing treated, preferably those with complementary activities that donot adversely affect each other. Alternatively, or in addition, thecomposition may comprise an agent that enhances its function, such as,for example, a cytotoxic agent, cytokine, chemotherapeutic agent, orgrowth-inhibitory agent. Such molecules are suitably present incombination in amounts that are effective for the purpose intended.

The active ingredients may also be entrapped in microcapsules prepared,for example, by coacervation techniques or by interfacialpolymerization, for example, hydroxymethylcellulose orgelatin-microcapsules and poly-(methylmethacylate) microcapsules,respectively, in colloidal drug delivery systems (for example,liposomes, albumin microspheres, microemulsions, nano-particles, andnanocapsules) or in macroemulsions. Such techniques are disclosed inRemington's Pharmaceutical Sciences, supra.

The formulations to be used for in vivo administration must be sterile.This is readily accomplished by filtration through sterile filtrationmembranes.

Sustained-release preparations may be prepared. Suitable examples ofsustained-release preparations include semipermeable matrices of solidhydrophobic polymers containing the antibody, which matrices are in theform of shaped articles, e.g., films, or microcapsules. Examples ofsustained-release matrices include polyesters, hydrogels (for example,poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides(U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and γethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradablelactic acid-glycolic acid copolymers such as the LUPRON DEPOT™(injectable microspheres composed of lactic acid-glycolic acid copolymerand leuprolide acetate), and poly-D-(−)-3-hydroxybutyric acid. Whilepolymers such as ethylene-vinyl acetate and lactic acid-glycolic acidenable release of molecules for over 100 days, certain hydrogels releaseproteins for shorter time periods. When encapsulated antibodies remainin the body for a long time, they may denature or aggregate as a resultof exposure to moisture at 37° C., resulting in a loss of biologicalactivity and possible changes in immunogenicity. Rational strategies canbe devised for stabilization depending on the mechanism involved. Forexample, if the aggregation mechanism is discovered to be intermolecularS—S bond formation through thio-disulfide interchange, stabilization maybe achieved by modifying sulfhydryl residues, lyophilizing from acidicsolutions, controlling moisture content, using appropriate additives,and developing specific polymer matrix compositions.

G. Uses for anti-PRO Antibodies

The anti-PRO antibodies of the invention have various utilities. Forexample, anti-PRO antibodies may be used in diagnostic assays for PRO,e.g., detecting its expression in specific cells, tissues, or serum.Various diagnostic assay techniques known in the art may be used, suchas competitive binding assays, direct or indirect sandwich assays andimmunoprecipitation assays conducted in either heterogeneous orhomogeneous phases [Zola, Monoclonal Antibodies: A Manual of Techniques,CRC Press, Inc. (1987) pp. 147-158]. The antibodies used in thediagnostic assays can be labeled with a detectable moiety. Thedetectable moiety should be capable of producing, either directly orindirectly, a detectable signal. For example, the detectable moiety maybe a radioisotope, such as ³H, ¹⁴C, ³²P, ³⁵S, or ¹²⁵I, a fluorescent orchemiluminescent compound, such as fluorescein isothiocyanate,rhodamine, or luciferin, or an enzyme, such as alkaline phosphatase,beta-galactosidase or horseradish peroxidase. Any method known in theart for conjugating the antibody to the detectable moiety may beemployed, including those methods described by Hunter et al., Nature,144:945 (1962); David et al., Biochemistry, 13: 1014 (1974); Pain etal., J. Immunol. Meth., 40:219 (1981); and Nygren, J. Histochem. andCytochem., 30:407 (1982).

Anti-PRO antibodies also are useful for the affinity purification of PROfrom recombinant cell culture or natural sources. In this process, theantibodies against PRO are immobilized on a suitable support, such aSephadex resin or filter paper, using methods well known in the art. Theimmobilized antibody then is contacted with a sample containing the PROto be purified, and thereafter the support is washed with a suitablesolvent that will remove substantially all the material in the sampleexcept the PRO, which is bound to the immobilized antibody. Finally, thesupport is washed with another suitable solvent that will release thePRO from the antibody.

The following examples are offered for illustrative purposes only, andare not intended to limit the scope of the present invention in any way.

All patent and literature references cited in the present specificationare hereby incorporated by reference in their entirety.

EXAMPLES

Commercially available reagents referred to in the examples were usedaccording to manufacturer's instructions unless otherwise indicated. Thesource of those cells identified in the following examples, andthroughout the specification, by ATCC accession numbers is the AmericanType Culture Collection, Manassas, Va.

Example 1 Extracellular Domain Homology Screening to Identify NovelPolypeptides and cDNA Encoding Therefor

The extracellular domain (ECD) sequences (including the secretion signalsequence, if any) from about 950 known secreted proteins from theSwiss-Prot public database were used to search EST databases. The ESTdatabases included public databases (e.g., Dayhoff, GenBank), andproprietary databases (e.g. LIFESEQ™, Incyte Pharmaceuticals, Palo Alto,Calif.). The search was performed using the computer program BLAST orBLAST2 (Altschul, and Gish, Methods in Enzymology 266: 460-80 (1996); asa comparison of the ECD protein sequences to a 6 frame translation ofthe EST sequences. Those comparisons with a Blast score of 70 (or insome cases 90) or greater that did not encode known proteins wereclustered and assembled into consensus DNA sequences with the program“phrap” (Phil Green, University of Washington, Seattle, Wash.).

Using this extracellular domain homology screen, consensus DNA sequenceswere assembled relative to the other identified EST sequences. Inaddition, the consensus DNA sequences obtained were often (but notalways) extended using repeated cycles of BLAST and phrap to extend theconsensus sequence as far as possible using the sources of EST sequencesdiscussed above.

Based upon the consensus sequences obtained as described above,oligonucleotides were then synthesized and used to identify by PCR acDNA library that contained the sequence of interest and for use asprobes to isolate a clone of the full-length coding sequence for a PROpolypeptide. Forward (.f) and reverse (.r) PCR primers generally rangefrom 20 to 30 nucleotides and are often designed to give a PCR productof about 100-1000 bp in length. The probe (.p) sequences are typically40-55 bp in length. In some cases, additional oligonucleotides aresynthesized when the consensus sequence is greater than about 1-1.5 kbp.In order to screen several libraries for a full-length clone, DNA fromthe libraries was screened by PCR amplification, as per Ausubel et al.,Current Protocols in Molecular Biology, with the PCR primer pair. Apositive library was then used to isolate clones encoding the gene ofinterest using the probe oligonucleotide and one of the primer pairs.

The cDNA libraries used to isolate the cDNA clones were constructed bystandard methods using commercially available reagents such as thosefrom Invitrogen, San Diego, Calif. The cDNA was primed with oligo dTcontaining a NotI site, linked with blunt to SalI hemikinased adaptors,cleaved with NotI, sized appropriately by gel electrophoresis, andcloned in a defined orientation into a suitable cloning vector (such aspRKB or pRKD; pRK5B is a precursor of pRK5D that does not contain theSfiI site; see, Holmes et al., Science, 253:1278-1280 (1991)) in theunique XhoI and NotI sites.

Example 2 Isolation of cDNA Clones Encoding PRO211 and PRO217

Consensus DNA sequences were assembled as described in Example 1 aboveand were designated as DNA28730 and DNA28760, respectively. Based onthese consensus sequences, oligonucleotides were synthesized and used toidentify by PCR a cDNA library that contained the sequences of interestand for use as probes to isolate a clone of the full-length codingsequence for the PRO211 and PRO217 polypeptides. The libraries used toisolate DNA32292-1131 and DNA33094-1131 were fetal lung libraries.

cDNA clones were sequenced in their entirety. The entire nucleotidesequences of PRO211 (DNA32292-1131) and PRO217 (UNQ191) are shown inFIG. 1 (SEQ ID NO:1) and FIG. 3 (SEQ ID NO:3), respectively. Thepredicted polypeptides are 353 and 379 amino acid in length,respectively, with respective molecular weights of approximately 38,190and 41,520 daltons.

The oligonucleotide sequences used in the above procedures were thefollowing:

28730.p (OLI 516) 5′-AGGGAGCACGGACAGTGTGCAGATGTGGACGAGTGCTCACTAGCA-3′(SEQ ID NO:5) 28730.f (OLI 517) 5′-AGAGTGTATCTCTGGCTACGC-3′ (SEQ IDNO:6) 28730.r (OLI 518) 5′-TAAGTCCGGCACATTACAGGTC-3′ (SEQ ID NO:7)28760.p (OLI 617)5′-CCCACGATGTATGAATGGTGGACTTTGTGTGACTCCTGGTTTCTGCATC-3′ (SEQ ID NO:8)28760.f (OLI 618) 5′-AAAGACGCATCTGCGAGTGTCC-3′ (SEQ ID NO:9) 28760.r(OLI 619) 5′-TGCTGATTTCACACTGCTCTCCC-3′ (SEQ ID NO:10)

Example 3 Isolation of cDNA Clones Encoding Human PRO230

A consensus DNA sequence was assembled relative to the other identifiedEST sequences as described in Example 1 above, wherein the consensussequence is designated herein as DNA30857. An EST proprietary toGenentech was employed in the consensus assembly. The EST is designatedas DNA20088 and has the nucleotide sequence shown in FIG. 7 (SEQ IDNO:13).

Based on the DNA30857 consensus sequence, oligonucleotides weresynthesized to identify by PCR a cDNA library that contained thesequence of interest and for use as probes to isolate a clone of thefull-length coding sequence for PRO230.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-TTCGAGGCCTCTGAGAAGTGGCCC-3′ (SEQ ID NO:14) reversePCR primer 5′-GGCGGTATCTCTCTGGCCTCCC-3′ (SEQ ID NO:15)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30857 sequence which had the followingnucleotide sequence

Hybridization Probe

5′-TTCTCCACAGCAGCTGTGGCATCCGATCGTGTCTCAATCCATTCTCTGGG-3′  (SEQ ID NO:16)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO230 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetallung tissue. DNA sequencing of the clones isolated as described abovegave the full-length DNA sequence for PRO230 (herein designated asDNA33223-1136 and the derived protein sequence for PRO230.

The entire nucleotide sequence of DNA33223-1136 is shown in FIG. 5 (SEQID NO:11). Clone DNA33223-1136 contains a single open reading frame withan apparent translational initiation site at nucleotide positions100-103 and ending at the stop codon at nucleotide positions 1501-1503(FIG. 5; SEQ ID NO:11). The predicted polypeptide precursor is 467 aminoacids long (FIG. 6).

Example 4 Isolation of cDNA Clones Encoding Human PRO232

A consensus DNA sequence was assembled relative to the other identifiedEST sequences as described in Example 1 above, wherein the consensussequence is designated herein as DNA30935. Based on the DNA30935consensus sequence, oligonucleotides were synthesized to identify by PCRa cDNA library that contained the sequence of interest and for use asprobes to isolate a clone of the full-length coding sequence for PRO232.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-TGCTGTGCTACTCCTGCAAAGCCC-3′ (SEQ ID NO:19) reversePCR primer 5′-TGCACAAGTCGGTGTCACAGCACG-3′ (SEQ ID NO:20)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30935 sequence which had the followingnucleotide sequence

Hybridization Probe

5′-AGCAACGAGGACTGCCTGCAGGTGGAGAACTGCACCCAGCTGGG-3′  (SEQ ID NO:21)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO232 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalkidney tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO232 [herein designated as DNA34435-1140]and the derived protein sequence for PRO232.

The entire nucleotide sequence of DNA34435-1140 is shown in FIG. 8 (SEQID NO:17). Clone DNA34435-1140 contains a single open reading frame withan apparent translational initiation site at nucleotide positions 17-19and ending at the stop codon at nucleotide positions 359-361 (FIG. 8;SEQ ID NO:17). The predicted polypeptide precursor is 114 amino acidslong (FIG. 9). Clone DNA34435-1140 has been deposited with ATCC on Sep.16, 1997 and is assigned ATCC deposit no. ATCC 209250.

Analysis of the amino acid sequence of the full-length PRO232 suggeststhat it possesses 35% sequence identity with a stem cell surface antigenfrom Gallus gallus.

Example 5 Isolation of cDNA Clones Encoding PRO187

A proprietary expressed sequence tag (EST) DNA database (LIFESEQ™,Incyte Pharmaceuticals, Palo Alto, Calif.) was searched and an EST(#843193) was identified which showed homology to fibroblast growthfactor (FGF-8) also known as androgen-induced growth factor. mRNA wasisolated from human fetal lung tissue using reagents and protocols fromInvitrogen, San Diego, Calif. (Fast Track 2). The cDNA libraries used toisolate the cDNA clones were constructed by standard methods usingcommercially available reagents (e.g., Invitrogen, San Diego, Calif. ,Life Technologies, Gaithersburg, Md.). The cDNA was primed with oligo dTcontaining a NotI site, linked with blunt to SalI hemikinased adaptors,cleaved with NotI, sized appropriately by gel electrophoresis, andcloned in a defined orientation into the cloning vector pRK5D usingreagents and protocols from Life Technologies, Gaithersburg, Md. (SuperScript Plasmid System). The double-stranded cDNA was sized to greaterthan 1000 bp and the SalI/NotI Tinkered cDNA was cloned into XhoI/NotIcleaved vector. pRK5D is a cloning vector that has an sp6 transcriptioninitiation site followed by an SfiI restriction enzyme site precedingthe XhoI/NotI cDNA cloning sites.

Several libraries from various tissue sources were screened by PCRamplification with the following oligonucleotide probes:

IN843193.f (OLI315) 5′-CAGTACGTGAGGGACCAGGGCGCCATGA-3′ (SEQ ID NO:24)IN843193.r (OLI 317) 5′-CCGGTGACCTGCACGTGCTTGCCA-3′ (SEQ ID NO:25)

A positive library was then used to isolate clones encoding the PRO187gene using one of the above oligonucleotides and the followingoligonucleotide probe:

IN843193.p (OLI 316) (SEQ ID NO:26)

 5′-GCGGATCTGCCGCCTGCTCANCTGGTCGGTCATGGCGCCCT-3′

A cDNA clone was sequenced in entirety. The entire nucleotide sequenceof PRO187 (DNA27864-1155) is shown in FIG. 10 (SEQ ID NO:22). CloneDNA27864-1155 contains a single open reading frame with an apparenttranslational initiation site at nucleotide position 1 (FIG. 10; SEQ IDNO:22). The predicted polypeptide precursor is 205 amino acids long.Clone DNA27864-1155 has been deposited with the ATCC (designation:DNA27864-1155) and is assigned ATCC deposit no. ATCC 209375.

Based on a BLAST and FastA sequence alignment analysis (using the ALIGNcomputer program) of the full-length sequence, the PRO187 polypeptideshows 74% amino acid sequence identity (Blast score 310) to humanfibroblast growth factor-8 (androgen-induced growth factor).

Example 6 Isolation of cDNA Clones Encoding PRO265

A consensus DNA sequence was assembled relative to other EST sequencesas described in Example 1 above using phrap. This consensus sequence isherein designated DNA33679. Based on the DNA33679 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO265.

PCR primers (two forward and one reverse) were synthesized:

forward PCR primer A: 5′-CGGTCTACCTGTATGGCAACC-3′ (SEQ ID NO:29);forward PCR primer B: 5′-GCAGGACAACCAGATAAACCAC-3′ (SEQ ID NO:30);reverse PCR primer 5′-ACGCAGATTTGAGAAGGCTGTC-3′ (SEQ ID NO:31)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA33679 sequence which had the followingnucleotide sequence

Hybridization Probe

5′-TTCACGGGCTGCTCTTGCCCAGCTCTTGAAGCTTGAAGAGCTGCAC-3′  (SEQ ID NO:32)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with PCRprimer pairs identified above. A positive library was then used toisolate clones encoding the PRO265 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human afetal brain library.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO265 [herein designated as DNA36350-1158](SEQ ID NO:27) and the derived protein sequence for PRO265.

The entire nucleotide sequence of DNA36350-1158 is shown in FIG. 12 (SEQID NO:27). Clone DNA36350-1158 contains a single open reading frame withan apparent translational initiation site at nucleotide positions352-354 and ending at the stop codon at positions 2332-2334 (FIG. 12).The predicted polypeptide precursor is 660 amino acids long (FIG. 13).Clone DNA36350-1158 has been deposited with ATCC and is assigned ATCCdeposit no. ATCC 209378.

Analysis of the amino acid sequence of the full-length PRO265polypeptide suggests that portions of it possess significant homology tothe fibromodulin and the fibromodulin precursor, thereby indicating thatPRO265 may be a novel member of the leucine rich repeat family,particularly related to fibromodulin.

Example 7 Isolation of cDNA Clones Encoding Human PRO219

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA28729. Based on the DNA28729 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO219.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-GTTGGATCTGGGCAACAATAAC-3′ (SEQ ID NO:35) reversePCR primer 5′-ATTGTTGTGCAGGCTGAGTTTAAG-3′ (SEQ ID NO:36)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA28729 sequence which had the followingnucleotide sequence

Hybridization Probe

5′-GCCTGTCAGTGTCCTGAGGGACACGTGCTCCGCAGCGATGGGAAG-3′  (SEQ ID NO:37)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO219 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalkidney tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO219 [herein designated as DNA32290-1164](SEQ ID NO:33) and the derived protein sequence for PRO219.

The entire nucleotide sequence of DNA32290-1164 is shown in FIG. 14 (SEQID NO:33). Clone DNA32290-1164 contains a single open reading frame withan apparent translational initiation site at nucleotide positions204-206 and ending at the stop codon at nucleotide positions 2949-2951(FIG. 14). The predicted polypeptide precursor is 915 amino acids long(FIG. 15). Clone DNA32290-1164 has been deposited with ATCC and isassigned ATCC deposit no. ATCC 209384.

Analysis of the amino acid sequence of the full-length PRO219polypeptide suggests that portions of it possess significant homology tothe mouse and human matrilin-2 precursor polypeptides.

Example 8 Isolation of cDNA Clones Encoding Human PRO246

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA30955. Based on the DNA30955 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO246.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-AGGGTCTCCAGGAGAAAGACTC-3′ (SEQ ID NO:40) reversePCR primer 5′-ATTGTGGGCCTTGCAGACATAGAC-3′ (SEQ ID NO:41)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30955 sequence which had the followingnucleotide sequence

Hybridization Probe

5′-GGCCACAGCATCAAAACCTTAGAACTCAATGTACTGGTTCCTCCAGCTCC-3′  (SEQ ID NO:42)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO246 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalliver tissue. DNA sequencing of the clones isolated as described abovegave the fill-length DNA sequence for PRO246 [herein designated asDNA35639-1172] (SEQ ID NO:38) and the derived protein sequence forPRO246.

The entire nucleotide sequence of DNA35639-1172 is shown in FIG. 16 (SEQID NO:38). Clone DNA35639-1172 contains a single open reading frame withan apparent translational initiation site at nucleotide positions126-128 and ending at the stop codon at nucleotide positions 1296-1298(FIG. 16). The predicted polypeptide precursor is 390 amino acids long(FIG. 17). Clone DNA35639-1172 has been deposited with ATCC and isassigned ATCC deposit no. ATCC 209396.

Analysis of the amino acid sequence of the full-length PRO246polypeptide suggests that it possess significant homology to the humancell surface protein HCAR, thereby indicating that PRO246 may be a novelcell surface virus receptor.

Example 9 Isolation of cDNA Clones Encoding Human PRO228

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA28758. An EST proprietary to Genentech was employedin the consensus assembly. This EST is shown in FIG. 20 (SEQ ID NO:50)and is herein designated as DNA21951.

Based on the DNA28758 consensus sequence, oligonucleotides weresynthesized: 1) to identify by PCR a cDNA library that contained thesequence of interest, and 2) for use as probes to isolate a clone of thefull-length coding sequence for PRO228.

PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-GGTAATGAGCTCCATTACAG-3′ (SEQ ID NO:51) forward PCRprimer 5′-GGAGTAGAAAGCGCATGG-3′ (SEQ ID NO:52) forward PCR primer5′-CACCTGATACCATGAATGGCAG-3′ (SEQ ID NO:53) reverse PCR primer5′-CGAGCTCGAATTAATTCG-3′ (SEQ ID NO:54) reverse PCR primer5′-GGATCTCCTGAGCTCAGG-3′ (SEQ ID NO:55) reverse PCR primer5′-CCTAGTTGAGTGATCCTTGTAAG-3′ (SEQ ID NO:56)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA28758 sequence which had the followingnucleotide sequence

Hybridization Probe

5′-ATGAGACCCACACCTCATGCCGCTGTAATCACCTGACACATTTTGCAATT-3′  (SEQ ID NO:57)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pairs identified above. A positive library was then used toisolate clones encoding the PRO228 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalkidney tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO228 [herein designated as DNA33092-1202](SEQ ID NO:48) and the derived protein sequence for PRO228.

The entire nucleotide sequence of DNA33092-1202 is shown in FIG. 18 (SEQID NO:48). Clone DNA33092-1202 contains a single open reading frame withan apparent translational initiation site at nucleotide positions 24-26of SEQ ID NO:48 and ending at the stop codon after nucleotide position2093 of SEQ ID NO:48. The predicted polypeptide precursor is 690 aminoacids long (FIG. 19). Clone DNA33092-1202 has been deposited with ATCCand is assigned ATCC deposit no. ATCC 209420.

Analysis of the amino acid sequence of the full-length PRO228polypeptide suggests that portions of it possess significant homology tothe secretin-related proteins CD97 and EMR1 as well as the secretinmember, latrophilin, thereby indicating that PRO228 may be a new memberof the secretin related proteins.

Example 10 Isolation of cDNA Clones Encoding Human PRO533

The EST sequence accession number AF007268, a murine fibroblast growthfactor (FGF-15) was used to search various public EST databases (e.g.,GenBank, Dayhoff, etc.). The search was performed using the computerprogram BLAST or BLAST2 as a comparison of the ECD protein sequences toa 6 frame translation of the EST sequences. The search resulted in a hitwith GenBank EST AA220994, which has been identified as stratagene NT2neuronal precursor 937230.

Based on the Genbank EST AA220994 sequence, oligonucleotides weresynthesized: 1) to identify by PCR a cDNA library that contained thesequence of interest, and 2) for use as probes to isolate a clone of thefull-length coding sequence. Forward and reverse PCR primers may rangefrom 20 to 30 nucleotides (typically about 24), and are designed to givea PCR product of 100-1000 bp in length. The probe sequences aretypically 40-55 bp (typically about 50) in length. In order to screenseveral libraries for a source of a full-length clone, DNA from thelibraries was screened by PCR amplification, as per Ausubel et al.,Current Protocols in Molecular Biology, with the PCR primer pair. Apositive library was then used to isolate clones encoding the gene ofinterest using the probe oligonucleotide and one of the PCR primers.

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified below. A positive library was then used toisolate clones encoding the PRO533 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalretina. The cDNA libraries used to isolated the cDNA clones wereconstructed by standard methods using commercially available reagents(e.g., Invitrogen, San Diego, Calif.; Clontech, etc.) The cDNA wasprimed with oligo dT containing a NotI site, linked with blunt to SalIhemikinased adaptors, cleaved with NotI, sized appropriately by gelelectrophoresis, and cloned in a defined orientation into a suitablecloning vector (such as pRKB or pRKD; pRK5B is a precursor of pRK5D thatdoes not contain the SfiI site; see, Holmes et al., Science,253:1278-1280 (1991)) in the unique XhoI and NotI sites.

A cDNA clone was sequenced in its entirety. The full length nucleotidesequence of PRO533 is shown in FIG. 21 (SEQ ID NO:58). CloneDNA49435-1219 contains a single open reading frame with an apparenttranslational initiation site at nucleotide positions 459-461 (FIG. 21;SEQ ID NO:58). The predicted polypeptide precursor is 216 amino acidslong. Clone DNA47412-1219 has been deposited with ATCC and is assignedATCC deposit no. ATCC 209480.

Based on a BLAST-2 and FastA sequence alignment analysis of thefull-length sequence, PRO533 shows amino acid sequence identity tofibroblast growth factor (53%). The oligonucleotide sequences used inthe above procedure were the following:

FGF15.forward: 5′-ATCCGCCCAGATGGCTACAATGTGTA-3′ (SEQ ID NO:60);FGF15.probe: 5′-GCCTCCCGGTCTCCCTGAGCAGTGCCAAACAGCGGCAGTGTA-3′ (SEQ IDNO:61); FGF15.reverse: 5′-CCAGTCCGGTGACAAGCCCAAA-3′ (SEQ ID NO:62).

Example 11 Isolation of cDNA Clones Encoding Human PRO245

A consensus DNA sequence was assembled relative to the other identifiedEST sequences as described in Example 1 above, wherein the consensussequence is designated herein as DNA30954.

Based on the DNA30954 consensus sequence, oligonucleotides weresynthesized to identify by PCR a cDNA library that contained thesequence of interest and for use as probes to isolate a clone of thefull-length coding sequence for PRO245.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-ATCGTTGTGAAGTTAGTGCCCC-3′ (SEQ ID NO:65) reversePCR primer 5′-ACCTGCGATATCCAACAGAATTG-3′ (SEQ ID NO:66)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30954 sequence which had the followingnucleotide sequence

Hybridization Probe

5′-GGAAGAGGATACAGTCACTCTGGAAGTATTAGTGGCTCCAGCAGTTCC-3′  (SEQ ID NO:67)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO245 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalliver tissue. DNA sequencing of the clones isolated as described abovegave the full-length DNA sequence for PRO245 [herein designated asDNA35638-1141] and the derived protein sequence for PRO245.

The entire nucleotide sequence of DNA35638-1141 is shown in FIG. 23 (SEQID NO:63). Clone DNA35638-1141 contains a single open reading frame withan apparent translational initiation site at nucleotide positions 89-91and ending at the stop codon at nucleotide positions 1025-1027 (FIG. 23;SEQ ID NO:63). The predicted polypeptide precursor is 312 amino acidslong (FIG. 24). Clone DNA35638-1141 has been deposited with ATCC on Sep.16, 1997 and is assigned ATCC deposit no. ATCC 209265.

Analysis of the amino acid sequence of the full-length PRO245 suggeststhat a portion of it possesses 60% amino acid identity with the humanc-myb protein and, therefore, may be a new member of the transmembraneprotein receptor tyrosine kinase family.

Example 12 Isolation of cDNA Clones Encoding Human PRO220, PRO221 andPRO227

(a) PRO220

A consensus DNA sequence was assembled relative to the other identifiedEST sequences as described in Example 1 above, wherein the consensussequence is designated herein as DNA28749. Based on the DNA28749consensus sequence, oligonucleotides were synthesized to identify by PCRa cDNA library that contained the sequence of interest and for use asprobes to isolate a clone of the full-length coding sequence for PRO220.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-TCACCTGGAGCCTTTATTGGCC-3′ (SEQ ID NO:74) reversePCR primer 5′-ATACCAGCTATAACCAGGCTGCG-3′ (SEQ ID NO:75)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA28749 sequence which had the followingnucleotide sequence:

Hybridization Probe

5′-CAACAGTAAGTGGTTTGATGCTCTTCCAAATCTAGAGATTCTGATGATTGGG-3′  (SEQ IDNO:76).

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO220 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetallung tissue. DNA sequencing of the clones isolated as described abovegave the full-length DNA sequence for PRO220 [herein designated asDNA32298-1132 and the derived protein sequence for PRO220.

The entire nucleotide sequence of DNA32298-1132 is shown in FIG. 25 (SEQID NO:68). Clone DNA32298-1132 contains a single open reading frame withan apparent translational initiation site at nucleotide positions480-482 and ending at the stop codon at nucleotide positions 2604-2606(FIG. 25). The predicted polypeptide precursor is 708 amino acids long(FIG. 26). Clone DNA32298-1132 has been deposited with ATCC and isassigned ATCC deposit no. ATCC 209257.

Analysis of the amino acid sequence of the full-length PRO220 shows ithas homology to member of the leucine rich repeat protein superfamily,including the leucine rich repeat protein and the neuronal leucine-richrepeat protein 1.

(b) PRO221

A consensus DNA sequence was assembled relative to the other identifiedEST sequences as described in Example 1 above, wherein the consensussequence is designated herein as DNA28756. Based on the DNA28756consensus sequence, oligonucleotides were synthesized to identify by PCRa cDNA library that contained the sequence of interest and for use asprobes to isolate a clone of the full-length coding sequence for PRO221.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-CCATGTGTCTCCTCCTACAAAG-3′ (SEQ ID NO:77) reversePCR primer 5′-GGGAATAGATGTGATCTGATTGG-3′ (SEQ ID NO:78)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA28756 sequence which had the followingnucleotide sequence:

Hybridization Probe

5′-CACCTGTAGCAATGCAAATCTCAAGGAAATACCTAGAGATCTTCCTCCTG-3′  (SEQ ID NO:79)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO221 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetallung tissue. DNA sequencing of the clones isolated as described abovegave the full-length DNA sequence for PRO221 [herein designated asDNA33089-1132 and the derived protein sequence for PRO221.

The entire nucleotide sequence of DNA33089-1132 is shown in FIG. 27 (SEQID NO:70). Clone DNA33089-1132 contains a single open reading frame withan apparent translational initiation site at nucleotide positions179-181 and ending at the stop codon at nucleotide positions 956-958(FIG. 27). The predicted polypeptide precursor is 259 amino acids long(FIG. 28). PRO221 is believed to have a transmembrane region at aminoacids 206-225. Clone DNA33089-1132 has been deposited with ATCC and isassigned ATCC deposit no. ATCC 209262.

Analysis of the amino acid sequence of the full-length PRO221 shows ithas homology to member of the leucine rich repeat protein superfamily,including the SLIT protein.

(c) PRO227

A consensus DNA sequence was assembled relative to the other identifiedEST sequences as described in Example 1 above, wherein the consensussequence is designated herein as DNA28740. Based on the DNA28740consensus sequence, oligonucleotides were synthesized to identify by PCRa cDNA library that contained the sequence of interest and for use asprobes to isolate a clone of the full-length coding sequence for PRO227.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-AGCAACCGCCTGAAGCTCATCC-3′ (SEQ ID NO:80) reversePCR primer 5′-AAGGCGCGGTGAAAGATGTAGACG-3′ (SEQ ID NO:81)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA28740 sequence which had the followingnucleotide sequence:

Hybridization Probe

5′GACTACATGTTTCAGGACCTGTACAACCTCAAGTCACTGGAGGTTGGCGA-3′  (SEQ ID NO:82).

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO227 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetallung tissue. DNA sequencing of the clones isolated as described abovegave the full-length DNA sequence for PRO227 [herein designated asDNA33786-1132 and the derived protein sequence for PRO227.

The entire nucleotide sequence of DNA33786-1132 is shown in FIG. 29 (SEQID NO:72). Clone DNA33786-1132 contains a single open reading frame withan apparent translational initiation site at nucleotide positions 33-35and ending at the stop codon at nucleotide positions 1893-1895 (FIG.29). The predicted polypeptide precursor is 620 amino acids long (FIG.30). PRO227 is believed to have a transmembrane region. CloneDNA33786-1132 has been deposited with ATCC and is assigned ATCC depositno. ATCC 209253.

Analysis of the amino acid sequence of the full-length PRO221 shows ithas homology to member of the leucine rich repeat protein superfamily,including the platelet glycoprotein V precursor and the humanglycoprotein V.

Example 13 Isolation of cDNA Clones Encoding Human PRO258

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA28746.

Based on the DNA28746 consensus sequence, oligonucleotides weresynthesized: 1) to identify by PCR a cDNA library that contained thesequence of interest, and 2) for use as probes to isolate a clone of thefull-length coding sequence for PRO258.

PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-GCTAGGAATTCCACAGAAGCCC-3′ (SEQ ID NO:85) reversePCR primer 5′-AACCTGGAATGTCACCGAGCTG-3′ (SEQ ID NO:86) reverse PCRprimer 5′-CCTAGCACAGTGACGAGGGACTTGGC-3′ (SEQ ID NO:87)

Additionally, synthetic oligonucleotide hybridization probes wereconstructed from the consensus DNA28740 sequence which had the followingnucleotide sequence:

Hybridization Probe

5′-AAGACACAGCCACCCTAAACTGTCAGTCTTCTGGGAGCAAGCCTGCAGCC-3′ (SEQ ID NO:88)5′-GCCCTGGCAGACGAGGGCGAGTACACCTGCTCAATCTTCACTATGCCTGT-3′ (SEQ ID NO:89)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO258 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetallung tissue. DNA sequencing of the clones isolated as described abovegave the full-length DNA sequence for PRO258 [herein designated asDNA35918-1174] (SEQ ID NO:83) and the derived protein sequence forPRO258.

The entire nucleotide sequence of DNA35918-1174 is shown in FIG. 31 (SEQID NO:83). Clone DNA35918-1174 contains a single open reading frame withan apparent translational initiation site at nucleotide positions147-149 of SEQ ID NO:83 and ending at the stop codon after nucleotideposition 1340 of SEQ ID NO:83 (FIG. 31). The predicted polypeptideprecursor is 398 amino acids long (FIG. 32). Clone DNA35918-1174 hasbeen deposited with ATCC and is assigned ATCC deposit no. ATCC 209402.

Analysis of the amino acid sequence of the full-length PRO258polypeptide suggests that portions of it possess significant homology tothe CRTAM and the poliovirus receptor and have an Ig domain, therebyindicating that PRO258 is a new member of the Ig superfamily.

Example 14 Isolation of cDNA Clones Encoding Human PRO266

An expressed sequence tag database was searched for ESTs having homologyto SLIT, resulting in the identification of a single EST sequencedesignated herein as T73996. Based on the T73996 EST sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO266.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-GTTGGATCTGGGCAACAATAAC-3′ (SEQ ID NO:92) reversePCR primer 5′-ATTGTTGTGCAGGCTGAGTTTAAG-3′ (SEQ ID NO:93)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed which had the following nucleotide sequence

Hybridization Probe

5′-GGTGGCTATACATGGATAGCAATTACCTGGACACGCTGTCCCGGG-3′  (SEQ ID NO:94)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO266 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalbrain tissue. DNA sequencing of the clones isolated as described abovegave the full-length DNA sequence for PRO266 [herein designated asDNA37150-1178] (SEQ ID NO:90) and the derived protein sequence forPRO266.

The entire nucleotide sequence of DNA37150-1178 is shown in FIG. 33 (SEQID NO:90). Clone DNA37150-1178 contains a single open reading frame withan apparent translational initiation site at nucleotide positions167-169 and ending at the stop codon after nucleotide position 2254 ofSEQ ID NO:90. The predicted polypeptide precursor is 696 amino acidslong (FIG. 34). Clone DNA37150-1178 has been deposited with ATCC and isassigned ATCC deposit no. ATCC 209401.

Analysis of the amino acid sequence of the full-length PRO266polypeptide suggests that portions of it possess significant homology tothe SLIT protein, thereby indicating that PRO266 may be a novel leucinerich repeat protein.

Example 15 Isolation of cDNA Clones Encoding Human PRO269

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA35705. Based on the DNA35705 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO269.

Forward and reverse PCR primers were synthesized:

forward PCR primer (.f1) 5′-TGGAAGGAGATGCGATGCCACCTG-3′ (SEQ ID NO:97)forward PCR primer (.f2) 5′-TGACCAGTGGGGAAGGACAG-3′ (SEQ ID NO:98)forward PCR primer (.f3) 5′-ACAGAGCAGAGGGTGCCTTG-3′ (SEQ ID NO:99)reverse PCR primer (.r1) 5′-TCAGGGACAAGTGGTGTCTCTCCC-3′ (SEQ ID NO:100)reverse PCR primer (.r2) 5′-TCAGGGAAGGAGTGTGCAGTTCTG-3′ (SEQ ID NO:101)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA35705 sequence which had the followingnucleotide sequence:

Hybridization Probe

5′-ACAGCTCCCGATCTCAGTTACTTGCATCGCGGACGAAATCGGCGCTCGCT-3′  (SEQ IDNO:102)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pairs identified above. A positive library was then used toisolate clones encoding the PRO269 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalkidney tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO269 [herein designated as DNA38260-1180](SEQ ID NO:95) and the derived protein sequence for PRO269.

The entire nucleotide sequence of DNA38260-1180 is shown in FIG. 35 (SEQID NO:95). Clone DNA38260-1180 contains a single open reading frame withan apparent translational initiation site at nucleotide positions314-316 and ending at the stop codon at nucleotide positions 1784-1786(FIG. 35; SEQ ID NO:95). The predicted polypeptide precursor is 490amino acids long (FIG. 36). Clone DNA38260-1180 has been deposited withATCC and is assigned ATCC deposit no. ATCC 209397.

Analysis of the amino acid sequence of the full-length PRO269 suggeststhat portions of it possess significant homology to the humanthrombomodulin proteins, thereby indicating that PRO269 may possess oneor more thrombomodulin-like domains.

Example 16 Isolation of cDNA Clones Encoding Human PRO287

A consensus DNA sequence encoding PRO287 was assembled relative to theother identified EST sequences as described in Example 1 above, whereinthe consensus sequence is designated herein as DNA28728. Based on theDNA28728 consensus sequence, oligonucleotides were synthesized toidentify by PCR a cDNA library that contained the sequence of interestand for use as probes to isolate a clone of the full-length codingsequence for PRO287.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-CCGATTCATAGACCTCGAGAGT-3′ (SEQ ID NO:105) reversePCR primer 5′-GTCAAGGAGTCCTCCACAATAC-3′ (SEQ ID NO:106)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA28728 sequence which had the followingnucleotide sequence

Hybridization Probe

5′-GTGTACAATGGCCATGCCAATGGCCAGCGCATTGGCCGCTTCTGT-3′  (SEQ ID NO:107)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO287 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalkidney tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO287 [herein designated as DNA39969-1185,SEQ ID NO:103] and the derived protein sequence for PRO287.

The entire nucleotide sequence of DNA39969-1185 is shown in FIG. 37 (SEQID NO:103). Clone DNA39969-1185 contains a single open reading framewith an apparent translational initiation site at nucleotide positions307-309 and ending at the stop codon at nucleotide positions 1552-1554(FIG. 37; SEQ ID NO:103). The predicted polypeptide precursor is 415amino acids long (FIG. 38). Clone DNA39969-1185 has been deposited withATCC and is assigned ATCC deposit no. ATCC 209400.

Analysis of the amino acid sequence of the full-length PRO287 suggeststhat it may possess one or more procollagen C-proteinase enhancerprotein precursor or procollagen C-proteinase enhancer protein-likedomains. Based on a BLAST and FastA sequence alignment analysis of thefull-length sequence, PRO287 shows nucleic acid sequence identity toprocollagen C-proteinase enhancer protein precursor and procollagenC-proteinase enhancer protein (47 and 54%, respectively).

Example 17 Isolation of cDNA Clones Encoding Human PRO214

A consensus DNA sequence was assembled using phrap as described inExample 1 above. This consensus DNA sequence is designated herein asDNA28744. Based on this consensus sequence, oligonucleotides weresynthesized: 1) to identify by PCR a cDNA library that contained thesequence of interest, and 2) for use as probes to isolate a clone of thefull-length coding sequence.

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified below. A positive library was then used toisolate clones encoding the PRO214 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetallung tissue.

A cDNA clone was sequenced in its entirety. The full length nucleotidesequence of DNA32286-1191 is shown in FIG. 39 (SEQ ID NO:108).DNA32286-1191 contains a single open reading frame with an apparenttranslational initiation site at nucleotide position 103 (FIG. 39; SEQID NO:108). The predicted polypeptide precursor is 420 amino acids long(SEQ ID NO:109).

Based on a BLAST and FastA sequence alignment analysis of thefull-length sequence, PRO214 polypeptide shows amino acid sequenceidentity to HT protein and/or Fibulin (49% and 38%, respectively).

The oligonucleotide sequences used in the above procedure were thefollowing:

28744.p (OLI555)5′-CCTGGCTATCAGCAGGTGGGCTCCAAGTGTCTCGATGTGGATGAGTGTGA-3′ (SEQ ID NO:110)28744.f (OLI556) 5′-ATTCTGCGTGAACACTGAGGGC-3′ (SEQ ID NO:111) 28744.r(OLI557) 5′-ATCTGCTTGTAGCCCTCGGCAC-3′ (SEQ ID NO:112)

Example 18 Isolation of cDNA Clones Encoding Human PRO317

A consensus DNA sequence was assembled using phrap as described inExample 1 above, wherein the consensus sequence is herein designated asDNA28722. Based on this consensus sequence, oligonucleotides weresynthesized: 1) to identify by PCR a cDNA library that contained thesequence of interest, and 2) for use as probes to isolate a clone of thefull-length coding sequence. The forward and reverse PCR primers,respectively, synthesized for this purpose were:

5′-AGGACTGCCATAACTTGCCTG (OLI489) (SEQ ID NO:115) and5′-ATAGGAGTTGAAGCAGCGCTGC (OLI490) (SEQ ID NO:116).

The probe synthesized for this purpose was:

5′-TGTGTGGACATAGACGAGTGCCGCTACCGCTACTGCCAGCACCGC (OLI488)  (SEQ IDNO:117)

mRNA for construction of the cDNA libraries was isolated from humanfetal kidney tissue.

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification, as perAusubel et al., Current Protocols in Molecular Biology (1989), with thePCR primer pair identified above. A positive library was then used toisolate clones containing the PRO317 gene using the probeoligonucleotide identified above and one of the PCR primers.

A cDNA clone was sequenced in its entirety. The entire nucleotidesequence of DNA33461-1199 (encoding PRO317) is shown in FIG. 41 (SEQ IDNO:113). Clone DNA33461-1199 contains a single open reading frame withan apparent translational initiation site at nucleotide positions 68-70(FIG. 41; SEQ ID NO: 113). The predicted polypeptide precursor is 366amino acids long. The predicted signal sequence is amino acids 1-18 ofFIG. 42 (SEQ ID NO:114). There is one predicted N-linked glycosylationsite at amino acid residue 160. Clone DNA33461-1199 has been depositedwith ATCC and is assigned ATCC deposit no. ATCC 209367.

Based on BLAST™ and FastA™ sequence alignment analysis (using the ALIGN™computer program) of the full-length PRO317sequence, PRO317 shows themost amino acid sequence identity to EBAF-1 (92%). The results alsodemonstrate a significant homology between human PRO317 and mouse LEFTYprotein. The C-terminal end of the PRO317 protein contains manyconserved sequences consistent with the pattern expected of a member ofthe TGF-superfamily.

In situ expression analysis in human tissues performed as describedbelow evidences that there is distinctly strong expression of the PRO317polypeptide in pancreatic tissue.

Example 19 Isolation of cDNA clones Encoding Human PRO301

A consensus DNA sequence designated herein as DNA35936 was assembledusing phrap as described in Example 1 above. Based on this consensussequence, oligonucleotides were synthesized: 1) to identify by PCR acDNA library that contained the sequence of interest, and 2) for use asprobes to isolate a clone of the full-length coding sequence.

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified below. A positive library was then used toisolate clones encoding the PRO301 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalkidney.

A cDNA clone was sequenced in its entirety. The full length nucleotidesequence of native sequence PRO301 is shown in FIG. 43 (SEQ ID NO:118).Clone DNA40628-1216 contains a single open reading frame with anapparent translational initiation site at nucleotide positions 52-54(FIG. 43; SEQ ID NO:118). The predicted polypeptide precursor is 299amino acids long with a predicted molecular weight of 32,583 daltons andpI of 8.29. Clone DNA40628-1216 has been deposited with ATCC and isassigned ATCC deposit No. ATCC 209432.

Based on a BLAST and FastA sequence alignment analysis of thefull-length sequence, PRO301 shows amino acid sequence identity to A33antigen precursor (30%) and coxsackie and adenovirus receptor protein(29%).

The oligonucleotide sequences used in the above procedure were thefollowing:

OLI2162 (35936.f1) 5′-TCGCGGAGCTGTGTTCTGTTTCCC-3′ (SEQ ID NO:120)OLI2163 (35936.p1)5′-TGATCGCGATGGGGACAAAGGCGCAAGCTCGAGAGGAAACTGTTGTGCCT-3′ (SEQ ID NO:121)OLI2164 (35936.f2) 5′-ACACCTGGTTCAAAGATGGG-3′ (SEQ ID NO:122) OLI2165(35936.r1) 5′-TAGGAAGAGTTGCTGAAGGCACGG-3′ (SEQ ID NO:123) OLI2166(35936.f3) 5′-TTGCCTTACTCAGGTGCTAC-3′ (SEQ ID NO:124) OLI2167 (35936.r2)5′-ACTCAGCAGTGGTAGGAAAG-3′ (SEQ ID NO:125)

Example 20 Isolation of cDNA Clones Encoding Human PRO224

A consensus DNA sequence assembled relative to the other identified ESTsequences as described in Example 1, wherein the consensus sequence isdesignated herein as DNA30845. Based on the DNA30845 consensus sequence,oligonucleotides were synthesized to identify by PCR a cDNA library thatcontained the sequence of interest and for use as probes to isolate aclone of the full-length coding sequence for PRO224.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-AAGTTCCAGTGCCGCACCAGTGGC-3′ (SEQ ID NO:128)reverse PCR primer 5′-TTGGTTCCACAGCCGAGCTCGTCG-3′ (SEQ ID NO:129)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30845 sequence which had the followingnucleotide sequence

Hybridization Probe

5′-GAGGAGGAGTGCAGGATTGAGCCATGTACCCAGAAAGGGCAATGCCCACC-3′  (SEQ IDNO:130)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO224 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalliver tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO224 [herein designated as DNA33221-1133]and the derived protein sequence for PRO224.

The entire nucleotide sequence of DNA33221-1133 is shown in FIG. 45 (SEQID NO:126). Clone DNA33221-1133 contains a single open reading framewith an apparent translational initiation site at nucleotide positions33-35 and ending at the stop codon at nucleotide positions 879-899 (FIG.45; SEQ ID NO:126). The start of a transmembrane region begins atnucleotide position 777. The predicted polypeptide precursor is 282amino acids long (FIG. 46). Clone DNA33221-1133 has been deposited withATCC and is assigned ATCC deposit no. ATCC 209263.

Analysis of the amino acid sequence of the full-length PRO224 suggeststhat it has homology to very low-density lipoprotein receptors,apolipoprotein E receptor and chicken oocyte receptors P95. Based on aBLAST and FastA sequence alignment analysis of the full-length sequence,PRO224 has amino acid identity to portions of these proteins in therange from 28% to 45%, and overall identity with these proteins in therange from 33% to 39%.

Example 21 Isolation of cDNA Clones Encoding Human PRO222

A consensus DNA sequence was assembled relative to the other identifiedEST sequences as described in Example 1 above, wherein the consensussequence is designated herein as DNA28771. Based on the DNA28771consensus sequence, oligonucleotides were synthesized to identify by PCRa cDNA library that contained the sequence of interest and for use asprobes to isolate a clone of the full-length coding sequence for PRO222.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-ATCTCCTATCGCTGCTTTCCCGG-3′ (SEQ ID NO:133) reversePCR primer 5′-AGCCAGGATCGCAGTAAAACTCC-3′ (SEQ ID NO:134)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA28771 sequence which had the followingnucleotide sequence:

Hybridization Probe

5′-ATTTAAACTTGATGGGTCTGCGTATCTTGAGTGCTTACAAAACCTTATCT-3′  (SEQ IDNO:135)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO222 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalkidney tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO222 [herein designated as DNA33107-1135]and the derived protein sequence for PRO222.

The entire nucleotide sequence of DNA33107-1135 is shown in FIG. 47 (SEQID NO:131). Clone DNA33107-1135 contains a single open reading framewith an apparent translational initiation site at nucleotide positions159-161 and ending at the stop codon at nucleotide positions 1629-1631(FIG. 47; SEQ ID NO:131). The predicted polypeptide precursor is 490amino acids long (FIG. 48). Clone DNA33107-1135 has been deposited withATCC and is assigned ATCC deposit no. ATCC 209251.

Based on a BLAST and FastA sequence alignment analysis of thefull-length sequence, PRO222 shows amino acid sequence identity to mousecomplement factor h precursor (25-26%), complement receptor (27-29%),mouse complement C3b receptor type 2 long form precursor (25-47%) andhuman hypothetical protein kiaa0247 (40%).

Example 22 Isolation of cDNA clones Encoding PRO234

A consensus DNA sequence was assembled (DNA30926) using phrap asdescribed in Example 1 above. Based on this consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence.

RNA for the construction of the cDNA libraries was isolated usingstandard isolation protocols, e.g., Ausubel et al., Current Protocols inMolecular Biology, from tissue or cell line sources or it was purchasedfrom commercial sources (e.g., Clontech). The cDNA libraries used toisolate the cDNA clones were constructed by standard methods (e.g.,Ausubel et al.) using commercially available reagents (e.g.,Invitrogen). This library was derived from 22 week old fetal braintissue.

A cDNA clone was sequenced in its entirety. The entire nucleotidesequence of PRO234 is shown in FIG. 49 (SEQ ID NO:136). The predictedpolypeptide precursor is 382 amino acids long and has a calculatedmolecular weight of approximately 43.1 kDa.

The oligonucleotide sequences used in the above procedure were thefollowing:

30926.p (OLI826):5′-GTTCATTGAAAACCTCTTGCCATCTGATGGTGACTTCTGGATTGGGCTCA-3′ (SEQ ID NO:138)30926.f (OL1827): 5′-AAGCCAAAGAAGCCTGCAGGAGGG-3′ (SEQ ID NO:139) 30926.r(OLI828): 5′-CAGTCCAAGCATAAAGGTCCTGGC-3′ (SEQ ID NO:140)

Example 23 Isolation of cDNA Clones Encoding Human PRO231

A consensus DNA sequence was assembled relative to the other identifiedEST sequences as described in Example 1 above, wherein the consensussequence was designated herein as DNA30933. Based on the DNA30933consensus sequence, oligonucleotides were synthesized to identify by PCRa cDNA library that contained the sequence of interest and for use asprobes to isolate a clone of the full-length coding sequence for PRO231.

Three PCR primers (two forward and one reverse) were synthesized:

forward PCR primer 1 5′-CCAACTACCAAAGCTGCTGGAGCC-3′ (SEQ ID NO:143)forward PCR primer 2 5′-GCAGCTCTATTACCACGGGAAGGA-3′ (SEQ ID NO:144)reverse PCR primer 5′-TCCTTCCCGTGGTAATAGAGCTGC-3′ (SEQ ID NO:145)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30933 sequence which had the followingnucleotide sequence

Hybridization Probe

5′-GGCAGAGAACCAGAGGCCGGAGGAGACTGCCTCTTTACAGCCAGG-3′  (SEQ ID NO:146)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pairs identified above. A positive library was then used toisolate clones encoding the PRO231 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalliver tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO231 [herein designated as DNA34434-1139]and the derived protein sequence for PRO231.

The entire nucleotide sequence of DNA34434-1139 is shown in FIG. 51 (SEQID NO:141). Clone DNA34434-1139 contains a single open reading framewith an apparent translational initiation site at nucleotide positions173-175 and ending at the stop codon at nucleotide positions 1457-1459(FIG. 51; SEQ ID NO:141). The predicted polypeptide precursor is 428amino acids long (FIG. 52). Clone DNA34434-1139 has been deposited withATCC on Sep. 16, 1997 and is assigned ATCC deposit no. ATCC 209252.

Analysis of the amino acid sequence of the full-length PRO231 suggeststhat it possesses 30% and 31% amino acid identity with the human and ratprostatic acid phosphatase precursor proteins, respectively.

Example 24 Isolation of cDNA Clones Encoding Human PRO229

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA28762. Based on the DNA28762 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO229.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-TTCAGCTCATCACCTTCACCTGCC-3′ (SEQ ID NO:149)reverse PCR primer 5′-GGCTCATACAAAATACCACTAGGG-3′ (SEQ ID NO:150)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA28762 sequence which had the followingnucleotide sequence

Hybridization Probe

5′-GGGCCTCCACCGCTGTGAAGGGCGGGTGGAGGTGGAACAGAAAGGCCAGT-3′  (SEQ IDNO:151)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO229 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalliver tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO229 [herein designated as DNA33100-1159](SEQ ID NO:147) and the derived protein sequence for PRO229.

The entire nucleotide sequence of DNA33100-1159 is shown in FIG. 53 (SEQID NO:147). Clone DNA33100-1159 contains a single open reading framewith an apparent translational initiation site at nucleotide positions98-100 and ending at the stop codon at nucleotide positions 1139-1141(FIG. 53). The predicted polypeptide precursor is 347 amino acids long(FIG. 54). Clone DNA33100-1159 has been deposited with ATCC and isassigned ATCC deposit no.ATCC 209377

Analysis of the amino acid sequence of the full-length PRO229polypeptide suggests that portions of it possess significant homology toantigen wc1.1, M130 antigen and CD6.

Example 25 Isolation of cDNA Clones Encoding Human PRO238

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described above in Example 1. This consensus sequence isherein designated DNA30908. Based on the DNA30908 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO238.

PCR primers (forward and reverse) were synthesized:

forward PCR primer 1 5′-GGTGCTAAACTGGTGCTCTGTGGC-3′ (SEQ ID NO:154)forward PCR primer 2 5′-CAGGGCAAGATGAGCATTCC-3′ (SEQ ID NO:155) reversePCR primer 5′-TCATACTGTTCCATCTCGGCACGC-3′ (SEQ ID NO:156)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30908 sequence which had the followingnucleotide sequence

Hybridization Probe

5′-AATGGTGGGGCCCTAGAAGAGCTCATCAGAGAACTCACCGCTTCTCATGC-3′  (SEQ IDNO:157)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO238 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalliver tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO238 and the derived protein sequence forPRO238.

The entire nucleotide sequence of DNA35600-1162 is shown in FIG. 55 (SEQID NO:152). Clone DNA35600-1162 contains a single open reading framewith an apparent translational initiation site at nucleotide positions134-136 and ending prior to the stop codon at nucleotide positions1064-1066 (FIG. 55). The predicted polypeptide precursor is 310 aminoacids long (FIG. 56). Clone DNA35600-1162 has been deposited with ATCCand is assigned ATCC deposit no. ATCC 209370.

Analysis of the amino acid sequence of the full-length PRO238polypeptide suggests that portions of it possess significant homology toreductase, particularly oxidoreductase, thereby indicating that PRO238may be a novel reductase.

Example 26 Isolation of cDNA Clones Encoding Human PRO233

The extracellular domain (ECD) sequences (including the secretionsignal, if any) of from about 950 known secreted proteins from theSwiss-Prot public protein database were used to search expressedsequence tag (EST) databases. The EST databases included public ESTdatabases (e.g., GenBank) and a proprietary EST DNA database (LIFESEQ™,Incyte Pharmaceuticals, Palo Alto, Calif.). The search was performedusing the computer program BLAST or BLAST2 (Altshul et al., Methods inEnzymology 266:460-480 (1996)) as a comparison of the ECD proteinsequences to a 6 frame translation of the EST sequence. Thosecomparisons resulting in a BLAST score of 70 (or in some cases 90) orgreater that did not encode known proteins were clustered and assembledinto consensus DNA sequences with the program “phrap” (Phil Green,University of Washington, Seattle, Wash.

An expressed sequence tag (EST) was identified by the EST databasesearch and a consensus DNA sequence was assembled relative to other ESTsequences using phrap. This consensus sequence is herein designatedDNA30945. Based on the DNA30945 consensus sequence, oligonucleotideswere synthesized: 1) to identify by PCR a cDNA library that containedthe sequence of interest, and 2) for use as probes to isolate a clone ofthe full-length coding sequence for PRO233.

Forward and reverse PCR primers were synthesized:

forward PCR primer 5′-GGTGAAGGCAGAAATTGGAGATG-3′ (SEQ ID NO:160) reversePCR primer 5′-ATCCCATGCATCAGCCTGTTTACC-3′ (SEQ ID NO:161)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30945 sequence which had the followingnucleotide sequence

Hybridization Probe

5′-GCTGGTGTAGTCTATACATCAGATTTGTTTGCTACACAAGATCCTCAG-3′  (SEQ ID NO:162)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO233 gene using the probe oligonucleotide.

RNA for construction of the cDNA libraries was isolated from human fetalbrain tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO233 [herein designated as DNA34436-1238](SEQ ID NO:158) and the derived protein sequence for PRO233.

The entire nucleotide sequence of DNA34436-1238 is shown in FIG. 57 (SEQID NO:158). Clone DNA34436-1238 contains a single open reading framewith an apparent translational initiation site at nucleotide positions101-103 and ending at the stop codon at nucleotide positions 1001-1003(FIG. 57). The predicted polypeptide precursor is 300 amino acids long(FIG. 58). The full-length PRO233 protein shown in FIG. 58 has anestimated molecular weight of about 32,964 daltons and a pI of about9.52. Clone DNA34436-1238 has been deposited with ATCC and is assignedATCC deposit no. ATCC 209523.

Analysis of the amino acid sequence of the full-length PRO233polypeptide suggests that portions of it possess significant homology toreductase proteins, thereby indicating that PRO233 may be a novelreductase.

Example 27 Isolation of cDNA Clones Encoding Human PRO223

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA30836. Based on the DNA30836 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO223.

PCR primer pairs (one forward and two reverse) were synthesized:

forward PCR primer 5′-TTCCATGCCACCTAAGGGAGACTC-3′ (SEQ ID NO:165)reverse PCR primer 1 5′-TGGATGAGGTGTGCAATGGCTGGC-3′ (SEQ ID NO:166)reverse PCR primer 2 5′-AGCTCTCAGAGGCTGGTCATAGGG-3′ (SEQ ID NO:167)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30836 sequence which had the followingnucleotide sequence

Hybridization Probe

5′-GTCGGCCCTTTCCCAGGACTGAACATGAAGAGTTATGCCGGCTTCCTCAC-3′  (SEQ IDNO:168)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO223 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalliver tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO223 [herein designated as DNA33206-1165](SEQ ID NO:163) and the derived protein sequence for PRO223.

The entire nucleotide sequence of DNA33206-1165 is shown in FIG. 59 (SEQID NO:163). Clone DNA33206-1165 contains a single open reading framewith an apparent translational initiation site at nucleotide positions97-99 and ending at the stop codon at nucleotide positions 1525-1527(FIG. 59). The predicted polypeptide precursor is 476 amino acids long(FIG. 60). Clone DNA33206-1165 has been deposited with ATCC and isassigned ATCC deposit no. ATCC 209372.

Analysis of the amino acid sequence of the full-length PRO223polypeptide suggests that it possesses significant homology to variousserine carboxypeptidase proteins, thereby indicating that PRO223 may bea novel serine carboxypeptidase.

Example 28 Isolation of cDNA Clones Encoding Human PRO235

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated “DNA30927”. Based on the DNA30927 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO235.

A pair of PCR primers (forward and reverse) were synthesized: forwardPCR primer 5′-TGGAATACCGCCTCCTGCAG-3′ (SEQ ID NO:171) reverse PCR primer5′-CTTCTGCCCTTTGGAGAAGATGGC-3′ (SEQ ID NO:172)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30927 sequence which had the followingnucleotide sequence

Hybridization Probe

5′-GGACTCACTGGCCCAGGCCTTCAATATCACCAGCCAGGACGAT-3′  (SEQ ID NO:173)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO235 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalliver tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO235 [herein designated as DNA35558-1167](SEQ ID NO:169) and the derived protein sequence for PRO235.

The entire nucleotide sequence of DNA35558-1167 is shown in FIG. 61 (SEQID NO:169). Clone DNA35558-1167 contains a single open reading framewith an apparent translational initiation site at nucleotide positions667-669 and ending at the stop codon at nucleotide positions 2323-2325(FIG. 61). The predicted polypeptide precursor is 552 amino acids long(FIG. 62). Clone DNA35558-1167 has been deposited with ATCC and isassigned ATCC deposit no. 209374.

Analysis of the amino acid sequence of the full-length PRO235polypeptide suggests that portions of it possess significant homology tothe human, mouse and Xenopus plexin protein, thereby indicating thatPRO235 may be a novel plexin protein.

Example 29 Isolation of cDNA Clones Encoding Human PRO236 and HumanPRO262

Consensus DNA sequences were assembled relative to other EST sequencesusing phrap as described in Example 1 above. These consensus sequencesare herein designated DNA30901 and DNA30847. Based on the DNA30901 andDNA30847 consensus sequences, oligonucleotides were synthesized: 1) toidentify by PCR a cDNA library that contained the sequence of interest,and 2) for use as probes to isolate a clone of the full-length codingsequence for PRO236 and PRO262, respectively.

Based upon the DNA30901 consensus sequence, a pair of PCR primers(forward and reverse) were synthesized:

forward PCR primer 5′-TGGCTACTCCAAGACCCTGGCATG-3′ (SEQ ID NO:178)reverse PCR primer 5′-TGGACAAATCCCCTTGCTCAGCCC-3′ (SEQ ID NO:179)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30901 sequence which had the followingnucleotide sequence

Hybridization Probe

5′-GGGCTTCACCGAAGCAGTGGACCTTTATTTTGACCACCTGATGTCCAGGG-3′  (SEQ IDNO:180)

Based upon the DNA30847 consensus sequence, a pair of PCR primers(forward and reverse) were synthesized:

forward PCR primer 5′-CCAGCTATGACTATGATGCACC-3′ (SEQ ID NO:181) reversePCR primer 5′-TGGCACCCAGAATGGTGTTGGCTC-3′ (SEQ ID NO:182)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30847 sequence which had the followingnucleotide sequence

Hybridization Probe

5′-CGAGATGTCATCAGCAAGTTCCAGGAAGTTCCTTTGGGACCTTTACCTCC-3′  (SEQ IDNO:183)

In order to screen several libraries for a source of full-length clones,DNA from the libraries was screened by PCR amplification with the PCRprimer pairs identified above. Positive libraries were then used toisolate clones encoding the PRO236 and PRO262 genes using the probeoligonucleotides and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetallung tissue for PRO236 and human fetal liver tissue for PRO262.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO236 [herein designated as DNA35599-1168](SEQ ID NO:174), the derived protein sequence for PRO236, thefill-length DNA sequence for PRO262 [herein designated as DNA36992-1168](SEQ ID NO:176) and the derived protein sequence for PRO262.

The entire nucleotide sequence of DNA35599-1168 is shown in FIG. 63 (SEQID NO:174). Clone DNA35599-1168 contains a single open reading framewith an apparent translational initiation site at nucleotide positions69-71 and ending at the stop codon at nucleotide positions 1977-1979(FIG. 63). The predicted polypeptide precursor is 636 amino acids long(FIG. 64). Clone DNA35599-1168 has been deposited with ATCC and isassigned ATCC deposit no. ATCC 209373.

The entire nucleotide sequence of DNA36992-1168 is shown in FIG. 65 (SEQID NO:176). Clone DNA36992-1168 contains a single open reading framewith an apparent translational initiation site at nucleotide positions240-242 and ending at the stop codon at nucleotide positions 2202-2204(FIG. 65). The predicted polypeptide precursor is 654 amino acids long(FIG. 66). Clone DNA36992-1168 has been deposited with ATCC and isassigned ATCC deposit no. ATCC 209382.

Analysis of the amino acid sequence of the full-length PRO236 and PRO262polypeptides suggests that portions of those polypeptides possesssignificant homology to β-galactosidase proteins derived from varioussources, thereby indicating that PRO236 and PRO262 may be novelβ-galactosidase homologs.

Example 30 Isolation of cDNA Clones Encoding Human PRO239

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA30909. Based on the DNA30909 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO239.

A pair of PCR primers (forward and reverse) were synthesized: forwardPCR primer 5′-CCTCCCTCTATTACCCATGTC-3′ (SEQ ID NO:186) reverse PCRprimer 5′-GACCAACTTTCTCTGGGAGTGAGG-3′ (SEQ ID NO:187)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30909 sequence which had the followingnucleotide sequence

Hybridization Probe

5′-GTCACTTTATTTCTCTAACAACAAGCTCGAATCCTTACCAGTGGCAG-3′  (SEQ ID NO:188)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO239 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetallung tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO239 [herein designated as DNA34407-1169](SEQ ID NO:184) and the derived protein sequence for PRO239.

The entire nucleotide sequence of DNA34407-1169 is shown in FIG. 67 (SEQID NO:184). Clone DNA34407-1169 contains a single open reading framewith an apparent translational initiation site at nucleotide positions72-74 and ending at the stop codon at nucleotide positions 1575-1577(FIG. 67). The predicted polypeptide precursor is 501 amino acids long(FIG. 68). Clone DNA34407-1169 has been deposited with ATCC and isassigned ATCC deposit no.ATCC 209383.

Analysis of the amino acid sequence of the full-length PRO239polypeptide suggests that portions of it possess significant homology tothe densin protein, thereby indicating that PRO239 may be a novelmolecule in the densin family.

Example 31 Isolation of cDNA Clones Encoding Human PRO257

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA28731. Based on the DNA28731 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO257.

A pair of PCR primers (forward and reverse) were synthesized: forwardPCR primer 5′-TCTCTATTCCAAACTGTGGCG-3′ (SEQ ID NO:191) reverse PCRprimer 5′-TTTGATGACGATTCGAAGGTGG-3′ (SEQ ID NO:192)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA28731 sequence which had the followingnucleotide sequence

Hybridization Probe

5′-GGAAGGATCCTTCACCAGCCCCAATTACCCAAAGCCGCATCCTGAGC-3′  (SEQ ID NO:193)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO257 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalkidney tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO257 [herein designated as DNA35841-1173(SEQ ID NO:189) and the derived protein sequence for PRO257.

The entire nucleotide sequence of DNA35841-1173 is shown in FIG. 69 (SEQID NO:189). Clone DNA35841-1173 contains a single open reading framewith an apparent translational initiation site at nucleotide positions964-966 and ending at the stop codon at nucleotide positions 2785-2787(FIG. 69). The predicted polypeptide precursor is 607 amino acids long(FIG. 70). Clone DNA35841-1173 has been deposited with ATCC and isassigned ATCC deposit no. ATCC 209403.

Analysis of the amino acid sequence of the full-length PRO257polypeptide suggests that portions of it possess significant homology tothe ebnerin protein, thereby indicating that PRO257 may be a novelprotein member related to the ebnerin protein.

Example 32 Isolation of cDNA Clones Encoding Human PRO260

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA30834. Based on the DNA30834 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO260.

PCR primers (forward and reverse) were synthesized: forward PCR primer:5′-TGGTTTGACCAGGCCAAGTTCGG-3′ (SEQ ID NO:196); reverse PCR primer A:5′-GGATTCATCCTCAAGGAAGAGCGG-3′ (SEQ ID NO:197); and reverse PCR primerB: 5′-AACTTGCAGCATCAGCCACTCTGC-3′ (SEQ ID NO:198)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30834 sequence which had the followingnucleotide sequence:

Hybridization Probe:

5′-TTCCGTGCCCAGCTTCGGTAGCGAGTGGTTCTGGTGGTATTGGCA-3′  (SEQ ID NO:199)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO260 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalkidney tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO260 [herein designated as DNA33470-1175](SEQ ID NO:194) and the derived protein sequence for PRO260.

The entire nucleotide sequence of DNA33470-1175 is shown in FIG. 71 (SEQID NO:194). Clone DNA33470-1175 contains a single open reading framewith an apparent translational initiation site at nucleotide positions67-69 and ending at the stop codon 1468-1470 (see FIG. 71). Thepredicted polypeptide precursor is 467 amino acids long (FIG. 72). CloneDNA33470-1175 has been deposited with ATCC and is assigned ATCC depositno. ATCC 209398.

Analysis of the amino acid sequence of the full-length PRO260polypeptide suggests that portions of it possess significant homology tothe alpha-1-fucosidase precursor, thereby indicating that PRO260 may bea novel fucosidase.

Example 33 Isolation of cDNA Clones Encoding Human PRO263

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA30914. Based on the DNA30914 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO263.

PCR primers (tow forward and one reverse) were synthesized:

forward PCR primer 1: 5′-GAGCTTTCCATCCAGGTGTCATGC-3′ (SEQ ID NO:202);forward PCR primer 2: 5′-GTCAGTGACAGTACCTACTCGG-3′ (SEQ ID NO:203);reverse PCR primer: 5′-TGGAGCAGGAGGAGTAGTAGTAGG-3′ (SEQ ID NO:204)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30914 sequence which had the followingnucleotide sequence:

Hybridization Probe:

5′-AGGAGGCCTGTAGGCTGCTGGGACTAAGTTTGGCCGGCAAGGACCAAGTT-3′  (SEQ IDNO:205)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO263 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalliver tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO263 [herein designated as DNA34431-1177](SEQ ID NO:200) and the derived protein sequence for PRO263.

The entire nucleotide sequence of DNA34431-1177 is shown in FIG. 73 (SEQID NO:200). Clone DNA34431-1177 contains a single open reading framewith an apparent translational initiation site at nucleotide positions160-162 of SEQ ID NO:200 and ending at the stop codon after thenucleotide at position 1126-1128 of SEQ ID NO:200 (FIG. 73). Thepredicted polypeptide precursor is 322 amino acids long (FIG. 74). CloneDNA34431-1177 has been deposited with ATCC and is assigned ATCC depositno. ATCC 209399.

Analysis of the amino acid sequence of the full-length PRO263polypeptide suggests that portions of it possess significant homology toCD44 antigen, thereby indicating that PRO263 may be a novel cell surfaceadhesion molecule.

Example 34 Isolation of cDNA Clones Encoding Human PRO270

A consensus DNA sequence was assembled relative to the other identifiedEST sequences as described in Example 1 above, wherein the consensussequence was designated herein as DNA35712. Based on the DNA35712consensus sequence, oligonucleotides were synthesized: 1) to identify byPCR a cDNA library that contained the sequence of interest, and 2) foruse as probes to isolate a clone of the full-length coding sequence forPRO270. Forward and reverse PCR primers were synthesized:

forward PCR primer (.f1) 5′-GCTTGGATATTCGCATGGGCCTAC-3′ (SEQ ID NO:208)forward PCR primer (.f2) 5′-TGGAGACAATATCCCTGAGG-3′ (SEQ ID NO:209)reverse PCR primer (.r1) 5′-AACAGTTGGCCACAGCATGGCAGG-3′ (SEQ ID NO:210)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA35712 sequence which had the followingnucleotide sequence

Hybridization Probe

5′-CCATTGATGAGGAACTAGAACGGGACAAGAGGGTCACTTGGATTGTGGAG-3′  (SEQ IDNO:211)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO270 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetallung tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO270 [herein designated as DNA39510-1181](SEQ ID NO:206) and the derived protein sequence for PRO270.

The entire nucleotide sequence of DNA39510-1181 is shown in FIG. 75 (SEQID NO:206). Clone DNA39510-1181 contains a single open reading framewith an apparent translational initiation site at nucleotide positions3-5 and ending at the stop codon at nucleotide positions 891-893 (FIG.75; SEQ ID NO:206). The predicted polypeptide precursor is 296 aminoacids long (FIG. 76). Clone DNA39510-1181 has been deposited with ATCCand is assigned ATCC deposit no. ATCC 209392.

Analysis of the amino acid sequence of the full-length PRO270 suggeststhat portions of it possess significant homology to thethioredoxin-protein, thereby indicating that the PRO270 protein may be anovel member of the thioredoxin family.

Example 35 Isolation of cDNA Clones Encoding Human PRO271

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA35737. Based on the DNA35737 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO271.

Forward and reverse PCR primers were synthesized:

forward PCR primer 1 5′-TGCTTCGCTACTGCCCTC-3′ (SEQ ID NO:214) forwardPCR primer 2 5′-TTCCCTTGTGGGTTGGAG-3′ (SEQ ID NO:215) forward PCR primer3 5′-AGGGCTGGAAGCCAGTTC-3′ (SEQ ID NO:216) reverse PCR primer 15′-AGCCAGTGAGGAAATGCG-3′ (SEQ ID NO:217) reverse PCR primer 25′-TGTCCAAAGTACACACACCTGAGG-3′ (SEQ ID NO:218)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA35737 sequence which had the followingnucleotide sequence

Hybridization Probe

5′-GATGCCACGATCGCCAAGGTGGGACAGCTCTTTGCCGCCTGGAAG-3′  (SEQ ID NO:219)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO271 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalbrain tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO271 [herein designated as DNA39423-1182](SEQ ID NO:212) and the derived protein sequence for PRO271.

The entire nucleotide sequence of DNA39423-1182 is shown in FIG. 77 (SEQID NO:212). Clone DNA39423-1182 contains a single open reading framewith an apparent translational initiation site at nucleotide positions101-103 and ending at the stop codon at nucleotide positions 1181-1183(FIG. 77). The predicted polypeptide precursor is 360 amino acids long(FIG. 78). Clone DNA39423-1182 has been deposited with ATCC and isassigned ATCC deposit no. ATCC 209387.

Analysis of the amino acid sequence of the full-length PRO271polypeptide suggests that it possess significant homology to theproteoglycan link protein, thereby indicating that PRO271 may be a linkprotein homolog.

Example 36 Isolation of cDNA Clones Encoding Human PRO272

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA36460. Based on the DNA36460 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO272.

Forward and reverse PCR primers were synthesized:

forward PCR primer (.f1) 5′-CGCAGGCCCTCATGGCCAGG-3′ (SEQ ID NO:222)forward PCR primer (.f2) 5′-GAAATCCTGGGTAATTGG-3′ (SEQ ID NO:223)reverse PCR primer 5′-GTGCGCGGTGCTCACAGCTCATC-3′ (SEQ ID NO:224)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA36460 sequence which had the followingnucleotide sequence

Hybridization Probe

5′-CCCCCCTGAGCGACGCTCCCCCATGATGACGCCCACGGGAACTTC-3′  (SEQ ID NO:225)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pairs identified above. A positive library was then used toisolate clones encoding the PRO272 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetallung tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO272 [herein designated as DNA40620-1183](SEQ ID NO:220) and the derived protein sequence for PRO272.

The entire nucleotide sequence of DNA40620-1183 is shown in FIG. 79 (SEQID NO:220). Clone DNA40620-1183 contains a single open reading framewith an apparent translational initiation site at nucleotide positions35-37 and ending at the stop codon at nucleotide positions 1019-1021(FIG. 79)- The predicted polypeptide precursor is 328 amino acids long(FIG. 80). Clone DNA40620-1183 has been deposited with ATCC and isassigned ATCC deposit no. ATCC 209388.

Analysis of the amino acid sequence of the full-length PRO272polypeptide suggests that portions of it possess significant homology tothe human and mouse reticulocalbin proteins, respectively, therebyindicating that PRO272 may be a novel reticulocalbin protein.

Example 37 Isolation of cDNA Clones Encoding Human PRO294

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA35731. Based on the DNA35731 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO294.

Forward and reverse PCR primers were synthesized:

forward PCR primer (.f1) 5′-TGGTCTCGCACACCGATC-3′ (SEQ ID NO:228)forward PCR primer (.f2) 5′-CTGCTGTCCACAGGGGAG-3′ (SEQ ID NO:229)forward PCR primer (.f3) 5′-CCTTGAAGCATACTGCTC-3′ (SEQ ID NO:230)forward PCR primer (.f4) 5′-GAGATAGCAATTTCCGCC-3′ (SEQ ID NO:231)reverse PCR primer (.r1) 5′-TTCCTCAAGAGGGCAGCC-3′ (SEQ ID NO:232)reverse PCR primer (.r2) 5′-CTTGGCACCAATGTCCGAGATTTC-3′ (SEQ ID NO:233)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA35731 sequence which had the followingnucleotide sequence

Hybridization Probe

5′-GCTCTGAGGAAGGTGACGCGCGGGGCCTCCGAACCCTFGGCCTTG-3′  (SEQ ID NO:234)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pairs identified above. A positive library was then used toisolate clones encoding the PRO294 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalbrain tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO294 [herein designated as DNA40604-1187](SEQ ID NO:226) and the derived protein sequence for PRO294.

The entire nucleotide sequence of DNA40604-1187 is shown in FIG. 81 (SEQID NO:226). Clone DNA40604-1187 contains a single open reading framewith an apparent translational initiation site at nucleotide positions396-398 and ending at the stop codon at nucleotide positions 2046-2048(FIG. 81). The predicted polypeptide precursor is 550 amino acids long(FIG. 82). Clone DNA40604-1187 has been deposited with ATCC and isassigned ATCC deposit no. 209394.

Analysis of the amino acid sequence of the full-length PRO294polypeptide suggests that portions of it possess significant homology toportions of various collagen proteins, thereby indicating that PRO294may be collagen-like molecule.

Example 38 Isolation of cDNA Clones Encoding Human PRO295

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA35814. Based on the DNA35814 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO295.

Forward and reverse PCR primers were synthesized:

forward PCR primer (.f1) 5′-GCAGAGCGGAGATGCAGCGGTG-3′ (SEQ ID NO:238)forward PCR primer (.f2) 5′-CCCAGCATGTACTGCCAG-3′ (SEQ ID NO:239)forward PCR primer (.f3) 5′-TTGGCAGCTTCATGGAGG-3′ (SEQ ID NO:240)forward PCR primer (.f4) 5′-CCTGGGCAAAAATGCAAC-3′ (SEQ ID NO:241)reverse PCR primer (.r1) 5′-CTCCAGCTCCTGGCGCACCTCCTC-3′ (SEQ ID NO:242)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA35814 sequence which had the followingnucleotide sequence

Hybridization Probe

5′-GGCTCTCAGCTACCGCGCAGGAGCGAGGCCACCCTCAATGAGATG-3′  (SEQ ID NO:243)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pairs identified above. A positive library was then used toisolate clones encoding the PRO295 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetallung tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO295 [herein designated as DNA38268-1188](SEQ ID NO:235) and the derived protein sequence for PRO295.

The entire nucleotide sequence of DNA38268-1188 is shown in FIG. 83 (SEQID NO:235). Clone DNA38268-1188 contains a single open reading framewith an apparent translational initiation site at nucleotide positions153-155 and ending at the stop codon at nucleotide positions 1202-1204(FIG. 83). The predicted polypeptide precursor is 350 amino acids long(FIG. 84). Clone DNA38268-1188 has been deposited with ATCC and isassigned ATCC deposit no. 209421.

Analysis of the amino acid sequence of the full-length PRO295polypeptide suggests that portions of it possess significant homology tothe integrin proteins, thereby indicating that PRO295 may be a novelintegrin.

Example 39 Isolation of cDNA Clones Encoding Human PRO293

The extracellular domain (ECD) sequences (including the secretionsignal, if any) of from about 950 known secreted proteins from theSwiss-Prot public protein database were used to search expressedsequence tag (EST) databases. The EST databases included public ESTdatabases (e.g., GenBank) and a proprietary EST DNA database (LIFESEQ™,Incyte Pharmaceuticals, Palo Alto, Calif.). The search was performedusing the computer program BLAST or BLAST2 (Altshul et al., Methods inEnzymology 266:460480 (1996)) as a comparison of the ECD proteinsequences to a 6 frame translation of the EST sequence. Thosecomparisons resulting in a BLAST score of 70 (or in some cases 90) orgreater that did not encode known proteins were clustered and assembledinto consensus DNA sequences with the program “phrap” (Phil Green,University of Washington, Seattle, Wash.;

Based on an expression tag sequence designated herein as T08294identified in the above analysis, oligonucleotides were synthesized: 1)to identify by PCR a cDNA library that contained the sequence ofinterest, and 2) for use as probes to isolate a clone of the full-lengthcoding sequence for PRO293.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-AACAAGGTAAGATGCCATCCTG-3′ (SEQ ID NO:246) reversePCR primer 5′-AAACTTGTCGATGGAGACCAGCTC-3′ (SEQ ID NO:247)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the expression sequence tag which had the followingnucleotide sequence

Hybridization Probe

5′-AGGGGCTGCAAAGCCTGGAGAGCCTCTCCTTCTATGACAACCAGC-3′  (SEQ ID NO:248)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO293 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalbrain tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO293 [herein designated as DNA37151-1193](SEQ ID NO:244) and the derived protein sequence for PRO293.

The entire nucleotide sequence of DNA37151-1193 is shown in FIG. 85 (SEQID NO:244). Clone DNA37151-1193 contains a single open reading framewith an apparent translational initiation site at nucleotide positions881-883 and ending at the stop codon after nucleotide position 3019 ofSEQ ID NO:244, FIG. 85). The predicted polypeptide precursor is 713amino acids long (FIG. 86). Clone DNA37151-1193 has been deposited withATCC and is assigned ATCC deposit no. ATCC 209393.

Analysis of the amino acid sequence of the full-length PRO293polypeptide suggests that portions of it possess significant homology tothe NLRR proteins, thereby indicating that PRO293 may be a novel NLRRprotein.

Example 40 Isolation of cDNA Clones Encoding Human PRO247

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA33480. Based on the DNA33480 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO247.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-CAACAATGAGGGCACCAAGC-3′ (SEQ ID NO:251) reversePCR primer 5′-GATGGCTAGGTTCTGGAGGTTCTG-3′ (SEQ ID NO:252)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the DNA33480 expression sequence tag which had thefollowing nucleotide sequence

Hybridization Probe

5′-CAACCTGCAGGAGATTGACCTCAAGGACAACAACCTCAAGACCATCG-3′  (SEQ ID NO:253)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO247 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalbrain tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO247 [herein designated as DNA35673-1201](SEQ ID NO:249) and the derived protein sequence for PRO247.

The entire nucleotide sequence of DNA35673-1201 is shown in FIG. 89 (SEQID NO:249). Clone DNA35673-1201 contains a single open reading framewith an apparent translational initiation site at nucleotide positions80-82 of SEQ ID NO:249 and ending at the stop codon after nucleotideposition 1717 of SEQ ID NO:249 (FIG. 89). The predicted polypeptideprecursor is 546 amino acids long (FIG. 88). Clone DNA35673-1201 hasbeen deposited with ATCC and is assigned ATCC deposit no. 209418.

Analysis of the amino acid sequence of the full-length PRO247polypeptide suggests that portions of it possess significant homology tothe densin molecule and KIAA0231, thereby indicating that PRO247 may bea novel leucine rich repeat protein.

Example 41 Isolation of cDNA Clones Encoding Human PRO302, PRO303,PRO304, PRO307 and PRO343

Consensus DNA sequences were assembled relative to other EST sequencesusing phrap as described in Example 1 above. These consensus sequencesare herein designated DNA35953, DNA35955, DNA35958, DNA37160 andDNA30895. Based on the DNA35953 consensus sequence, oligonucleotideswere synthesized: 1) to identify by PCR a cDNA library that containedthe sequence of interest, and 2) for use as probes to isolate a clone ofthe full-length coding sequence for PRO302.

PCR primers (forward and reverse) were synthesized:

forward PCR primer 1 5′-GTCCGCAAGGATGCCTACATGTTC-3′ (SEQ ID NO:264)forward PCR primer 2 5′-GCAGAGGTGTCTAAGGTTG-3′ (SEQ ID NO:265) reversePCR primer 5′-AGCTCTAGACCAATGCCAGCTTCC-3′ (SEQ ID NO:266)

Also, a synthetic oligonucleotide hybridization probe was constructedfrom the consensus DNA35953 sequence which had the following nucleotidesequence

Hybridization Probe

5′-GCCACCAACTCCTGCAAGAACTTCTCAGAACTGCCCCTGGTCATG-3′  (SEQ ID NO:267)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pairs identified above. A positive library was then used toisolate clones encoding the PRO302 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalkidney tissue (LIB228).

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO302 [herein designated as DNA40370-1217](SEQ ID NO:254) and the derived protein sequence for PRO302.

The entire nucleotide sequence of DNA40370-1217 is shown in FIG. 89 (SEQID NO:254). Clone DNA40370-1217 contains a single open reading framewith an apparent translational initiation site at nucleotide positions34-36 and ending at the stop codon at nucleotide positions 1390-1392(FIG. 89). The predicted polypeptide precursor is 452 amino acids long(FIG. 90). Various unique aspects of the PRO302 protein are shown inFIG. 90. Clone DNA40370-1217 has been deposited with the ATCC on Nov.21, 1997 and is assigned ATCC deposit no. ATCC 209485.

Based on the DNA35955 consensus sequence, oligonucleotides weresynthesized: 1) to identify by PCR a cDNA library that contained thesequence of interest, and 2) for use as probes to isolate a clone of thefull-length coding sequence for PRO303.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-GGGGAATTCACCCTATGACATTGCC-3′ (SEQ ID NO:268)reverse PCR primer 5′-GAATGCCCTGCAAGCATCAACTGG-3′ (SEQ ID NO:269)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA35955 sequence which had the followingnucleotide sequence:

Hybridization Probe

5′-GCACCTGTCACCTACACTAAACACATCCAGCCCATCTGTCTCCAGGCCTC-3′  (SEQ IDNO:270)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pairs identified above. A positive library was then used toisolate clones encoding the PRO303 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetallung tissue (LIB25).

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO303 [herein designated as DNA42551-1217](SEQ ID NO:256) and the derived protein sequence for PRO303.

The entire nucleotide sequence of DNA42551-1217 is shown in FIG. 91 (SEQID NO:256). Clone DNA42551-1217 contains a single open reading framewith an apparent translational initiation site at nucleotide positions20-22 and ending at the stop codon at nucleotide positions 962-964 (FIG.91). The predicted polypeptide precursor is 314 amino acids long (FIG.92). Various unique aspects of the PRO303 protein are shown in FIG. 92.Clone DNA42551-1217 has been deposited on Nov. 21, 1997 with the ATCCand is assigned ATCC deposit no. ATCC 209483.

Based on the DNA35958 consensus sequence, oligonucleotides weresynthesized: 1) to identify by PCR a cDNA library that contained thesequence of interest, and 2) for use as probes to isolate a clone of thefull-length coding sequence for PRO304.

Pairs of PCR primers (forward and reverse) were synthesized:

forward PCR primer 1 5′-GCGGAAGGGCAGAATGGGACTCCAAG-3′ (SEQ ID NO:271)forward PCR primer 2 5′-CAGCCCTGCCACATGTGC-3′ (SEQ ID NO:272) forwardPCR primer 3 5′-TACTGGGTGGTCAGCAAC-3′ (SEQ ID NO:273) reverse PCR primer5′-GGCGAAGAGCAGGGTGAGACCCCG-3′ (SEQ ID NO:274)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA35958 sequence which had the followingnucleotide sequence

Hybridization Probe

5′-GCCCTCATCCTCTCTGGCAAATGCAGTTACAGCCCGGAGCCCGAC-3′  (SEQ ID NO:275)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pairs identified above. A positive library was then used toisolate clones encoding the PRO304 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from 22 weekhuman fetal brain tissue (LIB153).

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO304 [herein designated as DNA39520-1217](SEQ ID NO:258) and the derived protein sequence for PRO304.

The entire nucleotide sequence of DNA39520-1217 is shown in FIG. 93 (SEQID NO:258). Clone DNA39520-1217 contains a single open reading framewith an apparent translational initiation site at nucleotide positions34-36 and ending at the stop codon at nucleotide positions 1702-1704(FIG. 93). The predicted polypeptide precursor is 556 amino acids long(FIG. 94). Various unique aspects of the PRO304 protein are shown inFIG. 94. Clone DNA39520-1217 has been deposited with ATCC on Nov. 21,1997 and is assigned ATCC deposit no. ATCC 209482.

Based on the DNA37160 consensus sequence, oligonucleotides weresynthesized: 1) to identify by PCR a cDNA library that contained thesequence of interest, and 2) for use as probes to isolate a clone of thefull-length coding sequence for PRO307.

Pairs of PCR primers (forward and reverse) were synthesized:

forward PCR primer 1 5′-GGGCAGGGATTCCAGGGCTCC-3′ (SEQ ID NO:276) forwardPCR primer 2 5′-GGCTATGACAGCAGGTTC-3′ (SEQ ID NO:277) forward PCR primer3 5′-TGACAATGACCGACCAGG-3′ (SEQ ID NO:278) reverse PCR primer5′-GCATCGCATTGCTGGTAGAGCAAG-3′ (SEQ ID NO:279)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA37160 sequence which had the followingnucleotide sequence

Hybridization Probe

5′-TTACAGTGCCCCCTGGAAACCCACTTGGCCTGCATACCGCCTCCC-3′  (SEQ ID NO:280)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pairs identified above. A positive library was then used toisolate clones encoding the PRO307 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalliver tissue (LIB229).

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO307 [herein designated as DNA41225-1217](SEQ ID NO:260) and the derived protein sequence for PRO307.

The entire nucleotide sequence of DNA41225-1217 is shown in FIG. 95 (SEQID NO:260). Clone DNA41225-1217 contains a single open reading framewith an apparent translational initiation site at nucleotide positions92-94 and ending at the stop codon at nucleotide positions 1241-1243(FIG. 95). The predicted polypeptide precursor is 383 amino acids long(FIG. 96). Various unique aspects of the PRO307 protein are shown inFIG. 96. Clone DNA41225-1217 has been deposited with ATCC on Nov. 21,1997 and is assigned ATCC deposit no. ATCC 209491.

Based on the DNA30895 consensus sequence, oligonucleotides weresynthesized: 1) to identify by PCR a cDNA library that contained thesequence of interest, and 2) for use as probes to isolate a clone of thefill-length coding sequence for PRO343.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-CGTCTCGAGCGCTCCATACAGTTCCCTTGCCCCA-3′ (SEQ IDNO:281) reverse PCR primer5′-TGGAGGGGGAGCGGGATGCTTGTCTGGGCGACTCCGGGGGCCCCCTCATGTGCCAGGTGGA-3′ (SEQID NO:282)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30895 sequence which had the followingnucleotide sequence

hybridization probe5′-CCCTCAGACCCTGCAGAAGCTGAAGGTTCCTATCATCGACTCGGAAGTCTGCAGCCATCTG (SEQ IDNO:283) TACTGGCGGGGAGCAGGACAGGGACCCATCACTGAGGACATGCTGTGTGCCGGCTACT-3′

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pairs identified above. A positive library was then used toisolate clones encoding the PRO343 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetallung tissue (LIB26).

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO343 [herein designated as DNA43318-1217](SEQ ID NO:262) and the derived protein sequence for PRO343.

The entire nucleotide sequence of DNA43318-1217 is shown in FIG. 97 (SEQID NO:262). Clone DNA43318-1217 contains a single open reading framewith an apparent translational initiation site at nucleotide positions53-55 and ending at the stop codon at nucleotide positions 1004-1006(FIG. 97). The predicted polypeptide precursor is 317 amino acids long(FIG. 98). Various unique aspects of the PRO343 protein are shown inFIG. 98. Clone DNA43318-1217 has been deposited with ATCC on Nov. 21,1997 and is assigned ATCC deposit no. ATCC 209481.

Example 42 Isolation of cDNA Clones Encoding Human PRO328

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA35615. Based on the DNA35615 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO328.

Forward and reverse PCR primers were synthesized:

forward PCR primer 5′-TCCTGCAGTTTCCTGATGC-3′ (SEQ ID NO:286) reverse PCRprimer 5′-CTCATATTGCACACCAGTAATTCG-3′ (SEQ ID NO:287)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA35615 sequence which had the followingnucleotide sequence

Hybridization Probe

5′ -ATGAGGAGAAACGTTTGATGGTGGAGCTGCACAACCTCTACCGGG-3′  (SEQ ID NO:288)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO328 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalkidney tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO328 [herein designated as DNA40587-1231](SEQ ID NO:284) and the derived protein sequence for PRO328.

The entire nucleotide sequence of DNA40587-1231 is shown in FIG. 99 (SEQID NO:284). Clone DNA40587-1231 contains a single open reading framewith an apparent translational initiation site at nucleotide positions15-17 and ending at the stop codon at nucleotide positions 1404-1406(FIG. 99). The predicted polypeptide precursor is 463 amino acids long(FIG. 100). Clone DNA40587-1231 has been deposited with ATCC and isassigned ATCC deposit no. ATCC 209438.

Analysis of the amino acid sequence of the full-length PRO328polypeptide suggests that portions of it possess significant homology tothe human glioblastoma protein and to the cysteine rich secretoryprotein thereby indicating that PRO328 may be a novel glioblastomaprotein or cysteine rich secretory protein.

Example 43 Isolation of cDNA Clones Encoding Human PRO335, PRO331 orPRO326

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA36685. Based on the DNA36685 consensus sequence,and Incyte EST sequence no. 2228990, oligonucleotides weresynthesized: 1) to identify by PCR a cDNA library that contained thesequence of interest, and 2) for use as probes to isolate a clone of thefull-length coding sequence for PRO335, PRO331 or PRO326.

Forward and reverse PCR primers were synthesized for the determinationof PRO335:

forward PCR primer 5′-GGAACCGAATCTCAGCTA-3′ (SEQ ID NO:295) forward PCRprimer 5′-CCTAAACTGAACTGGACCA-3′ (SEQ ID NO:296) forward PCR primer5′-GGCTGGAGACACTGAACCT-3′ (SEQ ID NO:297) forward PCR primer5′-ACAGCTGCACAGCTCAGAACAGTG-3′ (SEQ ID NO:298) reverse PCR primer5′-CATTCCCAGTATAAAAATTTTC-3′ (SEQ ID NO:299) reverse PCR primer5′-GGGTCTTGGTGAATGAGG-3′ (SEQ ID NO:300) reverse PCR primer5′-GTGCCTCTCGGTTACCACCAATGG-3′ (SEQ ID NO:301)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed for the determination of PRO335 which had the followingnucleotide sequence

Hybridization Probe

5′-GCGGCCACTGTTGGACCGAACTGTAACCAAGGGAGAAACAGCCGTCCTAC-3′  (SEQ IDNO:302)

Forward and reverse PCR primers were synthesized for the determinationof PRO331:

forward PCR primer 5′-GCCTTTGACAACCTTCAGTCACTAGTGG-3′ (SEQ ID NO:303)reverse PCR primer 5′-CCCCATGTGTCCATGACTGTTCCC-3′ (SEQ ID NO:304)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed for the determination of PRO331 which had the followingnucleotide sequence

Hybridization Probe

5′-TACTGCCTCATGACCTCTTCACTCCCTTGCATCATCTTAGAGCGG-3′  (SEQ ID NO:305)

Forward and reverse PCR primers were synthesized for the determinationof PRO326:

forward PCR primer 5′-ACTCCAAGGAAATCGGATCCGTTC-3′ (SEQ ID NO:306)reverse PCR primer 5′-TTAGCAGCTGAGGATGGGCACAAC-3′ (SEQ ID NO:307)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed for the determination of PRO331 which had the followingnucleotide sequence

Hybridization Probe

5′-GCCTTCACTGGTTTGGATGCATTGGAGCATCTAGACCTGAGTGACAACGC-3′  (SEQ IDNO:308)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pairs identified above. A positive library was then used toisolate clones encoding the PRO335, PRO331 or PRO326 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalkidney tissue (PRO335 and PRO326) and human fetal brain (PRO331).

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO335, PRO331 or PRO326 [herein designatedas SEQ ID NOS:289, 291 and 293, respectively; see FIGS. 101, 103 and105, respectively], and the derived protein sequence for PRO335, PRO331or PRO326 (see FIGS. 102, 104 and 106, respectively; SEQ ID NOS:290, 292and 294, respectively).

The entire nucleotide sequences are shown in FIGS. 101, 103 and 105,deposited with the ATCC on Jun. 2, 1998, Nov. 7, 1997 and Nov. 21, 1997,respectively.

Analysis of the amino acid sequence of the full-length PRO335, PRO331 orPRO326 polypeptide suggests that portions of it possess significanthomology to the LIG-1 protein, thereby indicating that PRO335, PRO331and PRO326 may be a novel LIG-1-related protein.

Example 44 Isolation of cDNA clones Encoding Human PRO332

Based upon an ECD homology search performed as described in Example 1above, a consensus DNA sequence designated herein as DNA36688 wasassembled. Based on the DNA36688 consensus sequence, oligonucleotideswere synthesized to identify by PCR a cDNA library that contained thesequence of interest and for use as probes to isolate a clone of thefull-length coding sequence for PRO332.

A pair of PCR primers (forward and reverse) were synthesized:

5′-GCATTGGCCGCGAGACTTTGCC-3′ (SEQ ID NO:311)5′-GCGGCCACGGTCCTTGGAAATG-3′ (SEQ ID NO:312)

A probe was also synthesized:

5′-TGGAGGAGCTCAACCTCAGCTACAACCGCATCACCAGCCCACAGG-3′  (SEQ ID NO:313)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO332 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from a humanfetal liver library (LIB229).

DNA sequencing of the clones isolated as described above gave thefill-length DNA sequence for DNA40982-1235 and the derived proteinsequence for PRO332.

The entire nucleotide sequence of DNA40982-1235 is shown in FIG. 107(SEQ ID NO:309). Clone DNA40982-1235 contains a single open readingframe (with an apparent translational initiation site at nucleotidepositions 342-344, as indicated in FIG. 107). The predicted polypeptideprecursor is 642 amino acids long, and has a calculated molecular weightof 72,067 (pI: 6.60). Clone DNA40982-1235 has been deposited with ATCCand is assigned ATCC deposit no. ATCC 209433.

Based on a BLAST and FastA sequence alignment analysis of thefull-length sequence, PRO332 shows about 30-40% amino acid sequenceidentity with a series of known proteoglycan sequences, including, forexample, fibromodulin and fibromodulin precursor sequences of variousspecies (FMOD_BOVIN, FMOD CHICK, FMOD_RAT, FMOD_MOUSE, FMOD_HUMAN,P_R36773), osteomodulin sequences (AB000114 1, AB007848_(—)1), decorinsequences (CFU83141_(—)1, OCU03394_(—)1, P_R42266, P_R42267, P_R42260,P_R89439), keratan sulfate proteoglycans (BTU48360_(—)1, AF022890_(—)1),corneal proteoglycan (AF022256_(—)1), and bone/cartilage proteoglycansand proteoglycane precursors (PGS1_BOVIN, PGS2_MOUSE, PGS2_HUMAN).

Example 45 Isolation of cDNA clones Encoding Human PRO334

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. Based on the consensussequence, oligonucleotides were synthesized: 1) to identify by PCR acDNA library that contained the sequence of interest, and 2) for use asprobes to isolate a clone of the full-length coding sequence for PRO334.

Forward and reverse PCR primers were synthesized for the determinationof PRO334:

forward PCR primer 5′-GATGGTTCCTGCTCAAGTGCCCTG-3′ (SEQ ID NO:316)reverse PCR primer 5′-TTGCACTTGTAGGACCCACGTACG-3′ (SEQ ID NO:317)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed for the determination of PRO334 which had the followingnucleotide sequence

Hybridization Probe

5′-CTGATGGGAGGACCTGTGTAGATGTTGATGAATGTGCTACAGGAAGAGCC-3′  (SEQ IDNO:318)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO334 gene using the probe oligonucleotideand one of the PCR primers.

Human fetal kidney cDNA libraries used to isolate the cDNA clones wereconstructed by standard methods using commercially available reagentssuch as those from Invitrogen, San Diego, Calif.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO334 [herein designated as DNA41379-1236](SEQ ID NO:314) and the derived protein sequence for PRO334.

The entire nucleotide sequence of DNA41379-1236 (also referred to asUNQ295) is shown in FIG. 109 (SEQ ID NO:314). Clone DNA41379-1236contains a single open reading frame with an apparent translationalinitiation site at nucleotide positions 203-205 and ending at the stopcodon at nucleotide positions 1730-1732 (FIG. 109). The predictedpolypeptide precursor is 509 amino acids long (FIG. 110). CloneDNA41379-1236 has been deposited with ATCC and is assigned ATCC depositno. ATCC 209488.

Analysis of the amino acid sequence of the full-length PRO334polypeptide suggests that portions of it possess significant homology tothe fibulin and fibrillin proteins, thereby indicating that PRO334 maybe a novel member of the EGF protein family.

Example 46 Isolation of cDNA Clones Encoding Human PRO346

A consensus DNA sequence was identified using phrap as described inExample 1 above. Specifically, this consensus sequence is hereindesignated DNA38240. Based on the DNA38240 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length PRO346 coding sequence.

RNA for construction of the cDNA libraries was isolated from human fetalliver. The cDNA libraries used to isolated the cDNA clones wereconstructed by standard methods using commercially available reagents(e.g., Invitrogen, San Diego, Calif.; Clontech, etc.) The cDNA wasprimed with oligo dT containing a NotI site, linked with blunt to SalIhemikinased adaptors, cleaved with NotI, sized appropriately by gelelectrophoresis, and cloned in a defined orientation into a suitablecloning vector (such as pRKB or pRKD; pRK5B is a precursor of pRK5D thatdoes not contain the SfiI site; see, Holmes et al., Science,253:1278-1280 (1991)) in the unique XhoI and NotI sites.

A cDNA clone was sequenced in entirety. The entire nucleotide sequenceof DNA44167-1243 is shown in FIG. 111 (SEQ ID NO:319). CloneDNA44167-1243 contains a single open reading frame with an apparenttranslational initiation site at nucleotide positions 64-66 (FIG. 111;SEQ ID NO:319). The predicted polypeptide precursor is 450 amino acidslong. Clone DNA44167-1243 has been deposited with ATCC and is assignedATCC deposit no. ATCC 209434 (designation DNA44167-1243).

Based on a BLAST, BLAST-2 and FastA sequence alignment analysis (usingthe ALIGN computer program) of the full-length sequence, PRO346 showsamino acid sequence identity to carcinoembryonic antigen (28%).

The oligonucleotide sequences used in the above procedure were thefollowing: OLI2691 (38240.f1)

5′-GATCCTGTCACAAAGCCAGTGGTGC-3′ (SEQ ID NO:321) OLI2693 (38240.r1)5′-CACTGACAGGGTTCCTCACCCAGG-3′ (SEQ ID NO:322) OLI2692 (3824O.p1)5′-CTCCCTCTGGGCTGTGGAGTATGTGGGGAACATGACCCTGACATG-3′ (SEQ ID NO:323)

Example 47 Isolation of cDNA Clones Encoding Human PRO268

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA35698. Based on the DNA35698 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO268.

Forward and reverse PCR primers were synthesized:

forward PCR primer 1 5′-TGAGGTGGGCAAGCGGCGAAATG-3′ (SEQ ID NO:326)forward PCR primer 2 5′-TATGTGGATCAGGACGTGCC-3′ (SEQ ID NO:327) forwardPCR primer 3 5′-TGCAGGGTTCAGTCTAGATTG-3′ (SEQ ID NO:328) reverse PCRprimer 5′-TTGAAGGACAAAGGCAATCTGCCAC-3′ (SEQ ID NO:329)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA35698 sequence which had the followingnucleotide sequence

Hybridization Probe

5′-GGAGTCTTGCAGTTCCCCTGGCAGTCCTGGTGCTGTTGCTTTGGG-3′  (SEQ ID NO:330)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO268 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetallung tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO268 [herein designated as DNA39427-1179](SEQ ID NO:324) and the derived protein sequence for PRO268.

The entire nucleotide sequence of DNA39427-1179 is shown in FIG. 113(SEQ ID NO:324). Clone DNA39427-1179 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 13-15 and ending at the stop codon at nucleotide positions853-855 (FIG. 113). The predicted polypeptide precursor is 280 aminoacids long (FIG. 114). Clone DNA39427-1179 has been deposited with ATCCand is assigned ATCC deposit no. ATCC 209395.

Analysis of the amino acid sequence of the fill-length PRO268polypeptide suggests that it possess significant homology to proteindisulfide isomerase, thereby indicating that PRO268 may be a novelprotein disulfide isomerase.

Example 48 Isolation of cDNA Clones Encoding Human PRO330

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA35730. Based on the DNA35730 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO330.

Forward and reverse PCR primers were synthesized:

forward PCR primer 1 5′-CCAGGCACAATTTCCAGA-3′ (SEQ ID NO:333) forwardPCR primer 2 5′-GGACCCTTCTGTGTGCCAG-3′ (SEQ ID NO:334) reverse PCRprimer 1 5′-GGTCTCAAGAACTCCTGTC-3′ (SEQ ID NO:335) reverse PCR primer 25′-ACACTCAGCATTGCCTGGTACTTG-3′ (SEQ ID NO:336)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus sequence which had the followingnucleotide sequence

Hybridization Probe

5′-GGGCACATGACTGACCTGATTTATGCAGAGAAAGAGCTGGTGCAG-3′  (SEQ ID NO:337)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO330 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalliver tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO330 [herein designated as DNA40603-1232](SEQ ID NO:331) and the derived protein sequence for PRO330.

The entire nucleotide sequence of DNA40603-1232 is shown in FIG. 115(SEQ ID NO:331). Clone DNA40603-1232 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 167-169 and ending at the stop codon at nucleotide positions1766-1768 (FIG. 115). The predicted polypeptide precursor is 533 aminoacids long (FIG. 116). Clone DNA40603-1232 has been deposited with ATCCand is assigned ATCC deposit no.ATCC 209486 on Nov. 21, 1997.

Analysis of the amino acid sequence of the full-length PRO330polypeptide suggests that portions of it possess significant homology tothe mouse prolyl 4-hydroxylase alpha subunit protein, thereby indicatingthat PRO330 may be a novel prolyl 4-hydroxylase alpha subunitpolypeptide.

Example 49 Isolation of cDNA Clones Encoding Human PRO310

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA40553. Based on the DNA40553 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNA librarythat contained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence for PRO310.

Forward and reverse PCR primers were synthesized:

forward PCR primer 1 5′-TCCCCAAGCCGTTCTAGACGCGG-3′ (SEQ ID NO:342)forward PCR primer 2 5′-CTGGTTCTTCCTTGCACG-3′ (SEQ ID NO:343) reversePCR primer 5′-GCCCAAATGCCCTAAGGCGGTATACCCC-3′ (SEQ ID NO:344)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus sequence which had the followingnucleotide sequence

Hybridization Probe

5′-GGGTGTGATGCTTGGAAGCATTTTCTGTGCTTTGATCACTATGCTAGGAC-3′  (SEQ IDNO:345)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO310 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalliver tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO310 [herein designated as DNA43046-1225(SEQ ID NO:340) and the derived protein sequence for PRO310 (SEQ IDNO:341).

The entire nucleotide sequence of DNA43046-1225 is shown in FIG. 119(SEQ ID NO:340). Clone DNA43046-1225 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 81-83 and ending at the stop codon at nucleotide positions1035-1037 (FIG. 119). The predicted polypeptide precursor is 318 aminoacids long (FIG. 120) and has a calculated molecular weight ofapproximately 36,382 daltons. Clone DNA43046-1225 has been depositedwith ATCC and is assigned ATCC deposit no. ATCC 209484.

Analysis of the amino acid sequence of the full-length PRO310polypeptide suggests that portions of it possess homology to C. elegansproteins and to fringe, thereby indicating that PRO310 may be involvedin development.

Example 50 Isolation of cDNA clones Encoding Human PRO339

An expressed sequence tag (EST) DNA database (LIFESEQ™, IncytePharmaceuticals, Palo Alto, Calif.) was searched and ESTs wereidentified. An assembly of Incyte clones and a consensus sequence wasformed using phrap as described in Example 1 above.

Forward and reverse PCR primers were synthesized based upon theassembly-created consensus sequence:

forward PCR primer 1 5′-GGGATGCAGGTGGTGTCTCATGGGG-3′ (SEQ ID NO:346)forward PCR primer 2 5′-CCCTCATGTACCGGCTCC-3′ (SEQ ID NO:347) forwardPCR primer 3 5′-GTGTGACACAGCGTGGGC-3′ (SEQ ID NO:43) forward PCR primer4 5′-GACCGGCAGGCTTCTGCG-3′ (SEQ ID NO:44) reverse PGR primer 15′-CAGCAGCTTCAGCCACCAGGAGTGG-3′ (SEQ ID NO:45) reverse PCR primer 25′-CTGAGCCGTGGGCTGCAGTCTCGC-3′ (SEQ ID NO:46)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus sequence which had the followingnucleotide sequence

Hybridization Probe

 5′-CCGACTACGACTGGTTCTTCATCATGCAGGATGACACATATGTGC-3′  (SEQ ID NO:47)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pairs identified above. A positive library was then used toisolate clones encoding the PRO339 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetalliver tissue.

A cDNA clone was sequenced in entirety. The entire nucleotide sequenceof DNA43466-1225 is shown in FIG. 117 (SEQ ID NO:338). CloneDNA43466-1225 contains a single open reading frame with an apparenttranslational initiation site at nucleotide positions 333-335 and endingat the stop codon found at nucleotide positions 2649-2651 (FIG. 117; SEQID NO:338). The predicted polypeptide precursor is 772 amino acids longand has a calculated molecular weight of approximately 86,226 daltons.Clone DNA43466-1225 has been deposited with ATCC and is assigned ATCCdeposit no. ATCC 209490.

Based on a BLAST and FastA sequence alignment analysis (using the ALIGNcomputer program) of the full-length sequence, PRO339 has homology to C.elegans proteins and collagen-like polymer sequences as well as tofringe, thereby indicating that PRO339 may be involved in development ortissue growth.

Example 51 Isolation of cDNA Clones Encoding Human PRO244

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. Based on this consensussequence, oligonucleotides were synthesized to identify by PCR a cDNAlibrary that contained the sequence of interest and for use as probes toisolate a clone of the full-length coding sequence for PRO244.

A pair of PCR primers (forward and reverse) were synthesized:

5′-TTCAGCTTCTGGGATGTAGGG-3′ (30923.f1) (SEQ ID NO:378)5′-TATTCCTACCATTTCACAAATCCG-3′ (30923.r1) (SEQ ID NO:379)

A probe was also synthesized:

5′-GGAGGACTGTGCCACCATGAGAGACTCTTCAAACCCAAGGCAAAATTGG-3′ (30923.p1)  (SEQID NO:380)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification with thePCR primer pair identified above. A positive library was then used toisolate clones encoding the PRO244 gene using the probe oligonucleotideand one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from a humanfetal kidney library. DNA sequencing of the clones isolated as describedabove gave the full-length DNA sequence and the derived protein sequencefor PRO244.

The entire nucleotide sequence of PRO244 is shown in FIG. 121 (SEQ IDNO:376). Clone DNA35668-1171 contains a single open reading frame withan apparent translational initiation site at nucleotide positions106-108 (FIG. 121). The predicted polypeptide precursor is 219 aminoacids long. Clone DNA35668-1171 has been deposited with ATCC (designatedas DNA35663-1171) and is assigned ATCC deposit no. ATCC209371. Theprotein has a cytoplasmic domain (aa 1-20), a transmembrane domain (aa21-46), and an extracellular domain (aa 47-219), with a C-lectin domainat aa 55-206.

Based on a BLAST and FastA sequence alignment analysis of thefull-length sequence, PRO244 shows notable amino acid sequence identityto hepatic lectin gallus gallus (43%), HIC hp120-binding C-type lectin(42%), macrophage lectin 2 (HUMHML2-1, 41%), and sequence PR32188 (44%).

Example 52 Use of PRO Polypeptide-Encoding Nucleic Acid as HybridizationProbes

The following method describes use of a nucleotide sequence encoding aPRO polypeptide as a hybridization probe.

DNA comprising the coding sequence of of a PRO polypeptide of interestas disclosed herein may be employed as a probe or used as a basis fromwhich to prepare probes to screen for homologous DNAs (such as thoseencoding naturally-occurring variants of the PRO polypeptide) in humantissue cDNA libraries or human tissue genomic libraries.

Hybridization and washing of filters containing either library DNAs isperformed under the following high stringency conditions. Hybridizationof radiolabeled PRO polypeptide-encoding nucleic acid-derived probe tothe filters is performed in a solution of 50% formamide, 5×SSC, 0.1%SDS, 0.1% sodium pyrophosphate, 50 mM sodium phosphate, pH 6.8,2×Denhardt's solution, and 10% dextran sulfate at 42° C. for 20 hours.Washing of the filters is performed in an aqueous solution of 0.1×SSCand 0. 1% SDS at 42° C.

DNAs having a desired sequence identity with the DNA encodingfull-length native sequence PRO polypeptide can then be identified usingstandard techniques known in the art.

Example 53 Expression of PRO Polypeptides in E. coli

This example illustrates preparation of an unglycosylated form of adesired PRO polypeptide by recombinant expression in E. coli.

The DNA sequence encoding the desired PRO polypeptide is initiallyamplified using selected PCR primers. The primers should containrestriction enzyme sites which correspond to the restriction enzymesites on the selected expression vector. A variety of expression vectorsmay be employed. An example of a suitable vector is pBR322 (derived fromE. coli; see Bolivar et al., Gene, 2:95 (1977)) which contains genes forampicillin and tetracycline resistance. The vector is digested withrestriction enzyme and dephosphorylated. The PCR amplified sequences arethen ligated into the vector. The vector will preferably includesequences which encode for an antibiotic resistance gene, a trppromoter, a polyhis leader (including the first six STII codons, polyhissequence, and enterokinase cleavage site), the specific PRO polypeptidecoding region, lambda transcriptional terminator, and an argU gene.

The ligation mixture is then used to transform a selected E. Coli strainusing the methods described in Sambrook et al., supra. Transformants areidentified by their ability to grow on LB plates and antibioticresistant colonies are then selected. Plasmid DNA can be isolated andconfirmed by restriction analysis and DNA sequencing.

Selected clones can be grown overnight in liquid culture medium such asLB broth supplemented with antibiotics. The overnight culture maysubsequently be used to inoculate a larger scale culture. The cells arethen grown to a desired optical density, during which the expressionpromoter is turned on.

After culturing the cells for several more hours, the cells can beharvested by centrifugation. The cell pellet obtained by thecentrifugation can be solubilized using various agents known in the art,and the solubilized PRO polypeptide can then be purified using a metalchelating column under conditions that allow tight binding of theprotein.

PRO187, PRO317, PRO301, PRO224 and PRO238 were successfully expressed inE. coli in a poly-His tagged form, using the following procedure. TheDNA encoding PRO187, PRO317, PRO301, PRO224 or PRO238 was initiallyamplified using selected PCR primers. The primers contained restrictionenzyme sites which correspond to the restriction enzyme sites on theselected expression vector, and other useful sequences providing forefficient and reliable translation initiation, rapid purification on ametal chelation column, and proteolytic removal with enterokinase. ThePCR-amplified, poly-His tagged sequences were then ligated into anexpression vector, which was used to transform an E. coli host based onstrain 52 (W3110 fuhA(tonA) lon galE rpoHts(htpRts) clpP(lacIq).Transformants were first grown in LB containing 50 mg/ml carbenicillinat 30° C. with shaking until an O.D.600 of 3-5 was reached. Cultureswere then diluted 50-100 fold into CRAP media (prepared by mixing 3.57 g(NH₄)₂SO₄, 0.71 g sodium citrate.2H2O, 1.07 g KCl, 5.36 g Difco yeastextract, 5.36 g Sheffield hycase SF in 500 mL water, as well as 110 mMMPOS, pH 7.3, 0.55% (w/v) glucose and 7 mM MgSO₄) and grown forapproximately 20-30 hours at 30° C. with shaking. Samples were removedto verify expression by SDS-PAGE analysis, and the bulk culture iscentrifuged to pellet the cells. Cell pellets were frozen untilpurification and refolding.

E. coli paste from 0.5 to 1 L fermentations (6-10 g pellets) wasresuspended in 10 volumes (w/v) in 7 M guanidine, 20 mM Tris, pH 8buffer. Solid sodium sulfite and sodium tetrathionate is added to makefinal concentrations of 0.1M and 0.02 M, respectively, and the solutionwas stirred overnight at 4° C. This step results in a denatured proteinwith all cysteine residues blocked by sulfitolization. The solution wascentrifuged at 40,000 rpm in a Beckman Ultracentifuge for 30 min. Thesupernatant was diluted with 3-5 volumes of metal chelate column buffer(6 M guanidine, 20 mM Tris, pH 7.4) and filtered through 0.22 micronfilters to clarify. Depending the clarified extract was loaded onto a 5ml Qiagen Ni-NTA metal chelate column equilibrated in the metal chelatecolumn buffer. The column was washed with additional buffer containing50 mM imidazole (Calbiochem, Utrol grade), pH 7.4. The protein waseluted with buffer containing 250 mM imidazole. Fractions containing thedesired protein were pooled and stored at 4° C. Protein concentrationwas estimated by its absorbance at 280 nm using the calculatedextinction coefficient based on its amino acid sequence.

The proteins were refolded by diluting sample slowly into freshlyprepared refolding buffer consisting of: 20 mM Tris, pH 8.6, 0.3 M NaCl,2.5 M urea, 5 mM cysteine, 20 mM glycine and 1 mM EDTA. Refoldingvolumes were chosen so that the final protein concentration was between50 to 100 micrograms/ml. The refolding solution was stirred gently at 4°C. for 12-36 hours. The refolding reaction was quenched by the additionof TFA to a final concentration of 0.4% (pH of approximately 3). Beforefurther purification of the protein, the solution was filtered through a0.22 micron filter and acetonitrile was added to 2-10% finalconcentration. The refolded protein was chromatographed on a Poros R1/Hreversed phase column using a mobile buffer of 0.1% TFA with elutionwith a gradient of acetonitrile from 10 to 80%. Aliquots of fractionswith A280 absorbance were analyzed on SDS polyacrylamide gels andfractions containing homogeneous refolded protein were pooled.Generally, the properly refolded species of most proteins are eluted atthe lowest concentrations of acetonitrile since those species are themost compact with their hydrophobic interiors shielded from interactionwith the reversed phase resin. Aggregated species are usually eluted athigher acetonitrile concentrations. In addition to resolving misfoldedforms of proteins from the desired form, the reversed phase step alsoremoves endotoxin from the samples.

Fractions containing the desired folded PRO187, PRO317, PRO301, PRO224and PRO238 proteins, respectively, were pooled and the acetonitrileremoved using a gentle stream of nitrogen directed at the solution.Proteins were formulated into 20 mM Hepes, pH 6.8 with 0.14 M sodiumchloride and 4% mannitol by dialysis or by gel filtration using G25Superfine (Pharmacia) resins equilibrated in the formulation buffer andsterile filtered.

Example 54 Expression of PRO Polypeptides in Mammalian Cells

This example illustrates preparation of a glycosylated form of a desiredPRO polypeptide by recombinant expression in mammalian cells.

The vector, pRK5 (see EP 307,247, published Mar. 15, 1989), is employedas the expression vector. Optionally, the PRO polypeptide-encoding DNAis ligated into pRK5 with selected restriction enzymes to allowinsertion of the PRO polypeptide DNA using ligation methods such asdescribed in Sambrook et al., supra. The resulting vector is calledpRK5-PRO polypeptide.

In one embodiment, the selected host cells may be 293 cells. Human 293cells (ATCC CCL 1573) are grown to confluence in tissue culture platesin medium such as DMEM supplemented with fetal calf serum andoptionally, nutrient components and/or antibiotics. About 10 μg pRK5-PROpolypeptide DNA is mixed with about 1 μg DNA encoding the VA RNA gene[Thimmappaya et al., Cell, 31:543 (1982)] and dissolved in 500 μl of 1mM Tris-HCl, 0.1 mM EDTA, 0.227 M CaCl₂. To this mixture is added,dropwise, 500 μl of 50 mM HEPES (pH 7.35), 280 mM NaCl, 1.5 mM NaPO₄,and a precipitate is allowed to form for 10 minutes at 25° C. Theprecipitate is suspended and added to the 293 cells and allowed tosettle for about four hours at 37° C. The culture medium is aspiratedoff and 2 ml of 20% glycerol in PBS is added for 30 seconds. The 293cells are then washed with serum free medium, fresh medium is added andthe cells are incubated for about 5 days.

Approximately 24 hours after the transfections, the culture medium isremoved and replaced with culture medium (alone) or culture mediumcontaining 200 μCi/ml ³⁵S-cysteine and 200 μCi/ml ³⁵S-methionine. Aftera 12 hour incubation, the conditioned medium is collected, concentratedon a spin filter, and loaded onto a 15% SDS gel. The processed gel maybe dried and exposed to film for a selected period of time to reveal thepresence of PRO polypeptide. The cultures containing transfected cellsmay undergo further incubation (in serum free medium) and the medium istested in selected bioassays.

In an alternative technique, PRO polypeptide may be introduced into 293cells transiently using the dextran sulfate method described bySomparyrac et al., Proc. Natl. Acad. Sci., 12:7575 (1981). 293 cells aregrown to maximal density in a spinner flask and 700 μg pRK5-PROpolypeptide DNA is added. The cells are first concentrated from thespinner flask by centrifugation and washed with PBS. The DNA-dextranprecipitate is incubated on the cell pellet for four hours. The cellsare treated with 20% glycerol for 90 seconds, washed with tissue culturemedium, and re-introduced into the spinner flask containing tissueculture medium, 5 μg/ml bovine insulin and 0.1 μg/ml bovine transferrin.After about four days, the conditioned media is centrifuged and filteredto remove cells and debris. The sample containing expressed PROpolypeptide can then be concentrated and purified by any selectedmethod, such as dialysis and/or column chromatography.

In another embodiment, PRO polypeptides can be expressed in CHO cells.The pRK5-PRO polypeptide can be transfected into CHO cells using knownreagents such as CaPO₄ or DEAE-dextran. As described above, the cellcultures can be incubated, and the medium replaced with culture medium(alone) or medium containing a radiolabel such as ³⁵S-methionine. Afterdetermining the presence of PRO polypeptide, the culture medium may bereplaced with serum free medium. Preferably, the cultures are incubatedfor about 6 days, and then the conditioned medium is harvested. Themedium containing the expressed PRO polypeptide can then be concentratedand purified by any selected method.

Epitope-tagged PRO polypeptide may also be expressed in host CHO cells.The PRO polypeptide may be subcloned out of the pRK5 vector. Thesubclone insert can undergo PCR to fuse in frame with a selected epitopetag such as a poly-his tag into a Baculovirus expression vector. Thepoly-his tagged PRO polypeptide insert can then be subcloned into a SV40driven vector containing a selection marker such as DHFR for selectionof stable clones. Finally, the CHO cells can be transfected (asdescribed above) with the SV40 driven vector. Labeling may be performed,as described above, to verify expression. The culture medium containingthe expressed poly-His tagged PRO polypeptide can then be concentratedand purified by any selected method, such as by Ni²⁺-chelate affinitychromatography.

PRO211, PRO217, PRO230, PRO219, PRO245, PRO221, PRO258, PRO301, PRO224,PRO222, PRO234, PRO229, PRO223, PRO328 and PRO332 were successfullyexpressed in CHO cells by both a transient and a stable expressionprocedure. In addition, PRO232, PRO265, PRO246, PRO228, PRO227, PRO220,PRO266, PRO269, PRO287, PRO214, PRO231, PRO233, PRO238, PRO244, PRO235,PRO236, PRO262, PRO239, PRO257, PRO260, PRO263, PRO270, PRO271, PRO272,PRO294, PRO295, PRO293, PRO247, PRO303 and PRO268 were successfullytransiently expressed in CHO cells.

Stable expression in CHO cells was performed using the followingprocedure. The proteins were expressed as an IgG construct(immunoadhesin), in which the coding sequences for the soluble forms(e.g. extracellular domains) of the respective proteins were fused to anIgG1 constant region sequence containing the hinge, CH2 and CH2 domainsand/or is a poly-His tagged form.

Following PCR amplification, the respective DNAs were subcloned in a CHOexpression vector using standard techniques as described in Ausubel etal., Current Protocols of Molecular Biology, Unit 3.16, John Wiley andSons (1997). CHO expression vectors are constructed to have compatiblerestriction sites 5′ and 3′ of the DNA of interest to allow theconvenient shuttling of cDNA's. The vector used expression in CHO cellsis as described in Lucas et al., Nucl. Acids Res. 24: 9 (1774-1779(1996), and uses the SV40 early promoter/enhancer to drive expression ofthe cDNA of interest and dihydrofolate reductase (DHFR). DHFR expressionpermits selection for stable maintenance of the plasmid followingtransfection.

Twelve micrograms of the desired plasmid DNA were introduced intoapproximately 10 million CHO cells using commercially availabletransfection reagents Superfect® (Quiagen), Dosper® or Fugene®(Boehringer Mannheim). The cells were grown and described in Lucas etal., supra. Approximately 3×10⁻⁷ cells are frozen in an ampule forfurther growth and production as described below.

The ampules containing the plasmid DNA were thawed by placement intowater bath and mixed by vortexing. The contents were pipetted into acentrifuge tube containing 10 mLs of media and centrifuged at 1000 rpmfor 5 minutes. The supernatant was aspirated and the cells wereresuspended in 10 mL of selective media (0.2 μm filtered PS20 with 5%0.2 μm diafiltered fetal bovine serum). The cells were then aliquotedinto a 100 mL spinner containing 90 mL of selective media. After 1-2days, the cells were transferred into a 250 mL spinner filled with 150mL selective growth medium and incubated at 37° C. After another 2-3days, a 250 mL, 500 mL and 2000 mL spinners were seeded with 3×10⁵cells/mL. The cell media was exchanged with fresh media bycentrifugation and resuspension in production medium. Although anysuitable CHO media may be employed, a production medium described inU.S. Pat. No. 5,122,469, issued Jun. 16, 1992 was actually used. 3 Lproduction spinner is seeded at 1.2×10⁶ cells/mL. On day 0, the cellnumber pH were determined. On day 1, the spinner was sampled andsparging with filtered air was commenced. On day 2, the spinner wassampled, the temperature shifted to 33° C., and 30 mL of 500 g/L glucoseand 0.6 mL of 10% antifoam (e.g., 35% polydimethylsiloxane emulsion, DowCorning 365 Medical Grade Emulsion). Throughout the production, pH wasadjusted as necessary to keep at around 7.2. After 10 days, or untilviability dropped below 70%, the cell culture was harvested bycentrifugtion and filtering through a 0.22 μm filter. The filtrate waseither stored at 4° C. or immediately loaded onto columns forpurification.

For the poly-His tagged constructs, the proteins were purified using aNi-NTA column (Qiagen). Before purification, imidazole was added to theconditioned media to a concentration of 5 mM. The conditioned media waspumped onto a 6 ml Ni-NTA column equilibrated in 20 mM Hepes, pH 7.4,buffer containing 0.3 M NaCl and 5 mM imidazole at a flow rate of 4-5ml/min. at 4° C. After loading, the column was washed with additionalequilibration buffer and the protein eluted with equilibration buffercontaining 0.25 M imidazole. The highly purified protein wassubsequently desalted into a storage buffer containing 10 mM Hepes, 0.14M NaCl and 4% mannitol, pH 6.8, with a 25 ml G25 Superfine (Pharmacia)column and stored at −80° C.

Immunoadhesin (Fc containing) constructs of were purified from theconditioned media as follows. The conditioned medium was pumped onto a 5ml Protein A column (Pharmacia) which had been equilibrated in 20 mM Naphosphate buffer, pH 6.8. After loading, the column was washedextensively with equilibration buffer before elution with 100 mM citricacid, pH 3.5. The eluted protein was immediately neutralized bycollecting 1 ml fractions into tubes containing 275 μL of 1 M Trisbuffer, pH 9. The highly purified protein was subsequently desalted intostorage buffer as described above for the poly-His tagged proteins. Thehomogeneity was assessed by SDS polyacrylamide gels and by N-terminalamino acid sequencing by Edman degradation.

PRO211, PRO217, PRO230, PRO232, PRO187, PRO265, PRO219, PRO246, PRO228,PRO533, PRO245, PRO221, PRO227, PRO220, PRO258, PRO266, PRO269, PRO287,PRO214, PRO317, PRO301, PRO224, PRO222, PRO234, PRO231, PRO229, PRO233,PRO238, PRO223, PRO235, PRO236, PRO262, PRO239, PRO257, PRO260, PRO263,PRO270, PRO271, PRO272, PRO294, PRO295, PRO293, PRO247, PRO304, PRO302,PRO307, PRO303, PRO343, PRO328, PRO326, PRO331, PRO332, PRO334, PRO346,PRO268, PRO330, PRO310 and PRO339 were also successfully transientlyexpressed in COS cells.

Example 55 Expression of PRO Polypeptides in Yeast

The following method describes recombinant expression of a desired PROpolypeptide in yeast.

First, yeast expression vectors are constructed for intracellularproduction or secretion of PRO polypeptides from the ADH2/GAPDHpromoter. DNA encoding a desired PRO polypeptide, a selected signalpeptide and the promoter is inserted into suitable restriction enzymesites in the selected plasmid to direct intracellular expression of thePRO polypeptide. For secretion, DNA encoding the PRO polypeptide can becloned into the selected plasmid, together with DNA encoding theADH2/GAPDH promoter, the yeast alpha-factor secretory signal/leadersequence, and linker sequences (if needed) for expression of the PROpolypeptide.

Yeast cells, such as yeast strain AB110, can then be transformed withthe expression plasmids described above and cultured in selectedfermentation media. The transformed yeast supernatants can be analyzedby precipitation with 10% trichloroacetic acid and separation bySDS-PAGE, followed by staining of the gels with Coomassie Blue stain.

Recombinant PRO polypeptide can subsequently be isolated and purified byremoving the yeast cells from the fermentation medium by centrifugationand then concentrating the medium using selected cartridge filters. Theconcentrate containing the PRO polypeptide may further be purified usingselected column chromatography resins.

Example 56 Expression of PRO Polypeptides in Baculovirus-Infected InsectCells

The following method describes recombinant expression of PROpolypeptides in Baculovirus-infected insect cells.

The desired PRO polypeptide is fused upstream of an epitope tagcontained with a baculovirus expression vector. Such epitope tagsinclude poly-his tags and immunoglobulin tags (like Fc regions of IgG).A variety of plasmids may be employed, including plasmids derived fromcommercially available plasmids such as pVL1393 (Novagen). Briefly, thePRO polypeptide or the desired portion of the PRO polypeptide (such asthe sequence encoding the extracellular domain of a transmembraneprotein) is amplified by PCR with primers complementary to the 5′ and3′regions. The 5′ primer may incorporate flanking (selected) restrictionenzyme sites. The product is then digested with those selectedrestriction enzymes and subcloned into the expression vector.

Recombinant baculovirus is generated by co-transfecting the aboveplasmid and BaculoGold™ virus DNA (Pharmingen) into Spodopterafrugiperda (“Sf9”) cells (ATCC CRL 1711) using lipofectin (commerciallyavailable from GIBCO-BRL). After 4-5 days of incubation at 28° C., thereleased viruses are harvested and used for further amplifications.Viral infection and protein expression is performed as described byO'Reilley et al., Baculovirus expression vectors: A laboratory Manual,Oxford: Oxford University Press (1994).

Expressed poly-his tagged PRO polypeptide can then be purified, forexample, by Ni² ⁺-chelate affinity chromatography as follows. Extractsare prepared from recombinant virus-infected Sf9 cells as described byRupert et al., Nature, 362:175-179 (1993). Briefly, Sf9 cells arewashed, resuspended in sonication buffer (25 mL Hepes, pH 7.9; 12.5 mMMgCl₂; 0.1 mM EDTA; 10% Glycerol; 0.1% NP-40; 0.4 M KCl), and sonicatedtwice for 20 seconds on ice. The sonicates are cleared bycentrifugation, and the supernatant is diluted 50-fold in loading buffer(50 mM phosphate, 300 mM NaCl, 10% Glycerol, pH 7.8) and filteredthrough a 0.45 μm filter. A Ni²⁺-NTA agarose column (commerciallyavailable from Qiagen) is prepared with a bed volume of 5 mL, washedwith 25 mL of water and equilibrated with 25 mL of loading buffer. Thefiltered cell extract is loaded onto the column at 0.5 mL per minute.The column is washed to baseline A₂₈₀ with loading buffer, at whichpoint fraction collection is started. Next, the column is washed with asecondary wash buffer (50 mM phosphate; 300 mM NaCl, 10% Glycerol, pH6.0), which elutes nonspecifically bound protein. After reaching A₂₈₀baseline again, the column is developed with a 0 to 500 mM Imidazolegradient in the secondary wash buffer. One mL fractions are collectedand analyzed by SDS-PAGE and silver staining or western blot withNi²⁺-NTA-conjugated to alkaline phosphatase (Qiagen). Fractionscontaining the eluted His₁₀-tagged PRO polypeptide are pooled anddialyzed against loading buffer.

Alternatively, purification of the IgG tagged (or Fc tagged) PROpolypeptide can be performed using known chromatography techniques,including for instance, Protein A or protein G column chromatography.

PRO211, PRO217, PRO230, PRO187, PRO265, PRO246, PRO228, PRO533, PRO245,PRO221, PRO220, PRO258, PRO266, PRO269, PRO287, PRO214, PRO301, PRO224,PRO222, PRO234, PRO231, PRO229, PRO235, PRO239, PRO257, PRO272, PRO294,PRO295, PRO328, PRO326, PRO331, PRO334, PRO346 and PRO310 weresuccessfully expressed in baculovirus infected Sf9 or high5 insectcells. While the expression was actually performed in a 0.5-2 L scale,it can be readily scaled up for larger (e.g. 8 L) preparations. Theproteins were expressed as an IgG construct (immunoadhesin), in whichthe protein extracellular region was fused to an IgG1 constant regionsequence containing the hinge, CH2 and CH3 domains and/or in poly-Histagged forms.

Following PCR amplification, the respective coding sequences weresubcloned into a baculovirus expression vector (pb.PH.IgG for IgGfusions and pb.PH.His.c for poly-His tagged proteins), and the vectorand Baculogold® baculovirus DNA (Pharmingen) were co-transfected into105 Spodoptera frugiperda (“Sf9”) cells (ATCC CRL 1711), usingLipofectin (Gibco BRL). pb.PH.IgG and pb.PH.His are modifications of thecommercially available baculovirus expression vector pVL1393(Pharmingen), with modified polylinker regions to include the His or Fctag sequences. The cells were grown in Hink's TNM-FH medium supplementedwith 10% FBS (Hyclone). Cells were incubated for 5 days at 28° C. Thesupernatant was harvested and subsequently used for the first viralamplification by infecting Sf9 cells in Hink's TNM-FH mediumsupplemented with 10% FBS at an approximate multiplicity of infection(MOI) of 10. Cells were incubated for 3 days at 28° C. The supernatantwas harvested and the expression of the constructs in the baculovirusexpression vector was determined by batch binding of 1 ml of supernatantto 25 mL of Ni-NTA beads (QIAGEN) for histidine tagged proteins orProtein-A Sepharose CL-4B beads (Pharmacia) for IgG tagged proteinsfollowed by SDS-PAGE analysis comparing to a known concentration ofprotein standard by Coomassie blue staining.

The first viral amplification supernatant was used to infect a spinnerculture (500 ml) of Sf9 cells grown in ESF-921 medium (ExpressionSystems LLC) at an approximate MOI of 0.1. Cells were incubated for 3days at 28° C. The supernatant was harvested and filtered. Batch bindingand SDS-PAGE analysis was repeated, as necessary, until expression ofthe spinner culture was confirmed.

The conditioned medium from the transfected cells (0.5 to 3 L) washarvested by centrifugation to remove the cells and filtered through0.22 micron filters. For the poly-His tagged constructs, the proteinconstruct were purified using a Ni-NTA column (Qiagen). Beforepurification, imidazole was added to the conditioned media to aconcentration of 5 mM. The conditioned media were pumped onto a 6 mlNi-NTA column equilibrated in 20 mM Hepes, pH 7.4, buffer containing 0.3M NaCl and 5 mM imidazole at a flow rate of 4-5 ml/min. at 4° C. Afterloading, the column was washed with additional equilibration buffer andthe protein eluted with equilibration buffer containing 0.25 Mimidazole. The highly purified protein was subsequently desalted into astorage buffer containing 10 mM Hepes, 0.14 M NaCl and 4% mannitol, pH6.8, with a 25 ml G25 Superfine (Pharmacia) column and stored at −80° C.

Immunoadhesin (Fc containing) constructs of proteins were purified fromthe conditioned media as follows. The conditioned media were pumped ontoa 5 ml Protein A column (Pharmacia) which had been equilibrated in 20 mMNa phosphate buffer, pH 6.8. After loading, the column was washedextensively with equilibration buffer before elution with 100 mM citricacid, pH 3.5. The eluted protein was immediately neutralized bycollecting 1 ml fractions into tubes containing 275 mL of 1 M Trisbuffer, pH 9. The highly purified protein was subsequently desalted intostorage buffer as described above for the poly-His tagged proteins. Thehomogeneity of the proteins was verified by SDS polyacrylamide gel (PEG)electrophoresis and N-terminal amino acid sequencing by Edmandegradation.

Example 57 Preparation of Antibodies that Bind to PRO Polypeptides

This example illustrates preparation of monoclonal antibodies which canspecifically bind to a PRO polypeptide.

Techniques for producing the monoclonal antibodies are known in the artand are described, for instance, in Goding, supra. Immunogens that maybe employed include purified PRO polypeptide, fusion proteins containingthe PRO polypeptide, and cells expressing recombinant PRO polypeptide onthe cell surface. Selection of the immunogen can be made by the skilledartisan without undue experimentation.

Mice, such as Balb/c, are immunized with the PRO polypeptide immunogenemulsified in complete Freund's adjuvant and injected subcutaneously orintraperitoneally in an amount from 1-100 micrograms. Alternatively, theimmunogen is emulsified in MPL-TDM adjuvant (Ribi ImmunochemicalResearch, Hamilton, Mont.) and injected into the animal's hind footpads. The immunized mice are then boosted 10 to 12 days later withadditional immunogen emulsified in the selected adjuvant. Thereafter,for several weeks, the mice may also be boosted with additionalimmunization injections. Serum samples may be periodically obtained fromthe mice by retro-orbital bleeding for testing in ELISA assays to detectanti-PRO polypeptide antibodies.

After a suitable antibody titer has been detected, the animals“positive” for antibodies can be injected with a final intravenousinjection of PRO polypeptide. Three to four days later, the mice aresacrificed and the spleen cells are harvested. The spleen cells are thenfused (using 35% polyethylene glycol) to a selected murine myeloma cellline such as P3×63AgU.1, available from ATCC, No. CRL 1597. The fusionsgenerate hybridoma cells which can then be plated in 96 well tissueculture plates containing HAT (hypoxanthine, aminopterin, and thymidine)medium to inhibit proliferation of non-fused cells, myeloma hybrids, andspleen cell hybrids.

The hybridoma cells will be screened in an ELISA for reactivity againstthe PRO polypeptide. Determination of “positive” hybridoma cellssecreting the desired monoclonal antibodies against the PRO polypeptideis within the skill in the art.

The positive hybridoma cells can be injected intraperitoneally intosyngeneic Balb/c mice to produce ascites containing the anti-PROpolypeptide monoclonal antibodies. Alternatively, the hybridoma cellscan be grown in tissue culture flasks or roller bottles. Purification ofthe monoclonal antibodies produced in the ascites can be accomplishedusing ammonium sulfate precipitation, followed by gel exclusionchromatography. Alternatively, affinity chromatography based uponbinding of antibody to protein A or protein G can be employed.

Example 58 Chimeric PRO Polypeptides

PRO polypeptides may be expressed as chimeric proteins with one or moreadditional polypeptide domains added to facilitate protein purification.Such purification facilitating domains include, but are not limited to,metal chelating peptides such as histidine-tryptophan modules that allowpurification on immobilized metals, protein A domains that allowpurification on immobilized immunoglobulin, and the domain utilized inthe FLAGS™ extension/affinity purification system (Immunex Corp.,Seattle Wash.). The inclusion of a cleavable linker sequence such asFactor XA or enterokinase (Invitrogen, San Diego Calif.) between thepurification domain and the PRO polypeptide sequence may be useful tofacilitate expression of DNA encoding the PRO polypeptide.

Example 59 Purification of PRO Polypeptides Using Specific Antibodies

Native or recombinant PRO polypeptides may be purified by a variety ofstandard techniques in the art of protein purification. For example,pro-PRO polypeptide, mature PRO polypeptide, or pre-PRO polypeptide ispurified by immunoaffinity chromatography using antibodies specific forthe PRO polypeptide of interest. In general, an immunoaffinity column isconstructed by covalently coupling the anti-PRO polypeptide antibody toan activated chromatographic resin.

Polyclonal immunoglobulins are prepared from immune sera either byprecipitation with ammonium sulfate or by purification on immobilizedProtein A (Pharmacia LKB Biotechnology, Piscataway, N.J.). Likewise,monoclonal antibodies are prepared from mouse ascites fluid by ammoniumsulfate precipitation or chromatography on immobilized Protein A.Partially purified immunoglobulin is covalently attached to achromatographic resin such as CnBr-activated SEPHAROSE™ (Pharmacia LKBBiotechnology). The antibody is coupled to the resin, the resin isblocked, and the derivative resin is washed according to themanufacturer's instructions.

Such an immunoaffinity column is utilized in the purification of PROpolypeptide by preparing a fraction from cells containing PROpolypeptide in a soluble form. This preparation is derived bysolubilization of the whole cell or of a subcellular fraction obtainedvia differential centrifugation by the addition of detergent or by othermethods well known in the art. Alternatively, soluble PRO polypeptidecontaining a signal sequence may be secreted in useful quantity into themedium in which the cells are grown.

A soluble PRO polypeptide-containing preparation is passed over theimmunoaffinity column, and the column is washed under conditions thatallow the preferential absorbance of PRO polypeptide (e.g., high ionicstrength buffers in the presence of detergent). Then, the column iseluted under conditions that disrupt antibody/PRO polypeptide binding(e.g., a low pH buffer such as approximately pH 2-3, or a highconcentration of a chaotrope such as urea or thiocyanate ion), and PROpolypeptide is collected.

Example 60 Drug Screening

This invention is particularly useful for screening compounds by usingPRO polypeptides or binding fragment thereof in any of a variety of drugscreening techniques. The PRO polypeptide or fragment employed in such atest may either be free in solution, affixed to a solid support, borneon a cell surface, or located intracellularly. One method of drugscreening utilizes eukaryotic or prokaryotic host cells which are stablytransformed with recombinant nucleic acids expressing the PROpolypeptide or fragment. Drugs are screened against such transformedcells in competitive binding assays. Such cells, either in viable orfixed form, can be used for standard binding assays. One may measure,for example, the formation of complexes between PRO polypeptide or afragment and the agent being tested. Alternatively, one can examine thediminution in complex formation between the PRO polypeptide and itstarget cell or target receptors caused by the agent being tested.

Thus, the present invention provides methods of screening for drugs orany other agents which can affect a PRO polypeptide-associated diseaseor disorder. These methods comprise contacting such an agent with an PROpolypeptide or fragment thereof and assaying (I) for the presence of acomplex between the agent and the PRO polypeptide or fragment, or (ii)for the presence of a complex between the PRO polypeptide or fragmentand the cell, by methods well known in the art. In such competitivebinding assays, the PRO polypeptide or fragment is typically labeled.After suitable incubation, free PRO polypeptide or fragment is separatedfrom that present in bound form, and the amount of free or uncomplexedlabel is a measure of the ability of the particular agent to bind to PROpolypeptide or to interfere with the PRO polypeptide/cell complex.

Another technique for drug screening provides high throughput screeningfor compounds having suitable binding affinity to a polypeptide and isdescribed in detail in WO 84/03564, published on Sep. 13, 1984. Brieflystated, large numbers of different small peptide test compounds aresynthesized on a solid substrate, such as plastic pins or some othersurface. As applied to a PRO polypeptide, the peptide test compounds arereacted with PRO polypeptide and washed. Bound PRO polypeptide isdetected by methods well known in the art. Purified PRO polypeptide canalso be coated directly onto plates for use in the aforementioned drugscreening techniques. In addition, non-neutralizing antibodies can beused to capture the peptide and immobilize it on the solid support.

This invention also contemplates the use of competitive drug screeningassays in which neutralizing antibodies capable of binding PROpolypeptide specifically compete with a test compound for binding to PROpolypeptide or fragments thereof. In this manner, the antibodies can beused to detect the presence of any peptide which shares one or moreantigenic determinants with PRO polypeptide.

Example 61 Rational Drug Design

The goal of rational drug design is to produce structural analogs ofbiologically active polypeptide of interest (i.e., a PRO polypeptide) orof small molecules with which they interact, e.g., agonists,antagonists, or inhibitors. Any of these examples can be used to fashiondrugs which are more active or stable forms of the PRO polypeptide orwhich enhance or interfere with the function of the PRO polypeptide invivo (c.f., Hodgson, Bio/Technology, 9: 19-21(1991)).

In one approach, the three-dimensional structure of the PRO polypeptide,or of an PRO polypeptide-inhibitor complex, is determined by x-raycrystallography, by computer modeling or, most typically, by acombination of the two approaches. Both the shape and charges of the PROpolypeptide must be ascertained to elucidate the structure and todetermine active site(s) of the molecule. Less often, useful informationregarding the structure of the PRO polypeptide may be gained by modelingbased on the structure of homologous proteins. In both cases, relevantstructural information is used to design analogous PRO polypeptide-likemolecules or to identify efficient inhibitors. Useful examples ofrational drug design may include molecules which have improved activityor stability as shown by Braxton and Wells, Biochemistry, 31:7796-7801(1992) or which act as inhibitors, agonists, or antagonists of nativepeptides as shown by Athauda et al., J. Biochem. 113:742-746 (1993).

It is also possible to isolate a target-specific antibody, selected byfunctional assay, as described above, and then to solve its crystalstructure. This approach, in principle, yields a pharmacore upon whichsubsequent drug design can be based. It is possible to bypass proteincrystallography altogether by generating anti-idiotypic antibodies(anti-ids) to a functional, pharmacologically active antibody. As amirror image of a mirror image, the binding site of the anti-ids wouldbe expected to be an analog of the original receptor. The anti-id couldthen be used to identify and isolate peptides from banks of chemicallyor biologically produced peptides. The isolated peptides would then actas the pharmacore.

By virtue of the present invention, sufficient amounts of the PROpolypeptide may be made available to perform such analytical studies asX-ray crystallography. In addition, knowledge of the PRO polypeptideamino acid sequence provided herein will provide guidance to thoseemploying computer modeling techniques in place of or in addition tox-ray crystallography.

Example 62 Diagnostic Test Using PRO317 Polypeptide-Specific Antibodies

Particular anti-PRO317 polypeptide antibodies are useful for thediagnosis of prepathologic conditions, and chronic or acute diseasessuch as gynecological diseases or ischemic diseases which arecharacterized by differences in the amount or distribution of PRO317.PRO317 has been found to be expressed in human kidney and is thus likelyto be associated with abnormalities or pathologies which affect thisorgan. Further, since it is so closely related to EBAF-1, it is likelyto affect the endometrium and other genital tissues. Further, due tolibrary sources of certain ESTs, it appears that PRO317 may be involvedas well in forming blood vessels and hence to be a modulator ofangiogenesis.

Diagnostic tests for PRO317 include methods utilizing the antibody and alabel to detect PRO317 in human body fluids, tissues, or extracts ofsuch tissues. The polypeptide and antibodies of the present inventionmay be used with or without modification. Frequently, the polypeptideand antibodies will be labeled by joining them, either covalently ornoncovalently, with a substance which provides for a detectable signal.A wide variety of labels and conjugation techniques are known and havebeen reported extensively in both the scientific and patent literature.Suitable labels include radionuclides, enzymes, substrates, cofactors,inhibitors, fluorescent agents, chemiluminescent agents, magneticparticles, and the like. Patents teaching the use of such labels includeU.S. Pat. Nos. 3,817,837; 3,850,752; 3,939,350; 3,996,345; 4,277,437;4,275,149; and 4,366,241. Also, recombinant immunoglobulins may beproduced as shown in U.S. Pat. No. 4,816,567.

A variety of protocols for measuring soluble or membrane-bound PRO317,using either polyclonal or monoclonal antibodies specific for thatPRO317, are known in the art. Examples include enzyme-linkedimmunosorbent assay (ELISA), radioimmunoassay (RIA), radioreceptor assay(RRA), and fluorescent activated cell sorting (FACS). A two-sitemonoclonal-based immunoassay utilizing monoclonal antibodies reactive totwo non-interfering epitopes on PRO317 is preferred, but a competitivebinding assay may be employed. These assays are described, among otherplaces, in Maddox et al. J Exp. Med., 158:1211 (1983).

Example 63 Identification of PRO317 Receptors

Purified PRO317 is useful for characterization and purification ofspecific cell surface receptors and other binding molecules. Cells whichrespond to PRO317 by metabolic changes or other specific responses arelikely to express a receptor for PRO317. Such receptors include, but arenot limited to, receptors associated with and activated by tyrosine andserine/threonine kinases. See Kolodziejczyk and Hall, supra, for areview on known receptors for the TGF-superfamily. Candidate receptorsfor this superfamily fall into two primary groups, termed type I andtype II receptors. Both types are serine/threonine kinases. Uponactivation by the appropriate ligand, type I and type II receptorsphysically interact to form hetero-oligomers and subsequently activateintracellular signaling cascades, ultimately regulating genetranscription and expression. In addition, TGF-binds to a third receptorclass, type III, a membrane-anchored proteoglycan lacking the kinaseactivity typical of signal transducing molecules.

PRO317 receptors or other PRO317-binding molecules may be identified byinteraction with radiolabeled PRO317. Radioactive labels may beincorporated into PRO317 by various methods known in the art. Apreferred embodiment is the labeling of primary amino groups in PRO317with ¹²⁵I Bolton-Hunter reagent (Bolton and Hunter, Biochem. J., 133:529(1973)), which has been used to label other polypeptides withoutconcomitant loss of biological activity (Hebert et al., J. Biol. Chem.266:18989 (1991); McColl et al., J. Immunol., 150:45504555 (1993)).Receptor-bearing cells are incubated with labeled PRO317. The cells arethen washed to removed unbound PRO317, and receptor-bound PRO317 isquantified. The data obtained using different concentrations of PRO317are used to calculate values for the number and affinity of receptors.

Labeled PRO317 is useful as a reagent for purification of its specificreceptor. In one embodiment of affinity purification, PRO317 iscovalently coupled to a chromatography column. Receptor-bearing cellsare extracted, and the extract is passed over the column. The receptorbinds to the column by virtue of its biological affinity for PRO317. Thereceptor is recovered from the column and subjected to N-terminalprotein sequencing. This amino acid sequence is then used to designdegenerate oligonucleotide probes for cloning the receptor gene.

In an alternative method, mRNA is obtained from receptor-bearing cellsand made into a cDNA library. The library is transfected into apopulation of cells, and those cells expressing the receptor areselected using fluorescently labeled PRO317. The receptor is identifiedby recovering and sequencing recombinant DNA from highly labeled cells.

In another alternative method, antibodies are raised against the surfaceof receptor bearing cells, specifically monoclonal antibodies. Themonoclonal antibodies are screened to identify those which inhibit thebinding of labeled PRO317. These monoclonal antibodies are then used inaffinity purification or expression cloning of the receptor.

Soluble receptors or other soluble binding molecules are identified in asimilar manner. Labeled PRO317 is incubated with extracts or otherappropriate materials derived from the uterus. After incubation, PRO317complexes larger than the size of purified PRO317 are identified by asizing technique such as size-exclusion chromatography or densitygradient centrifugation and are purified by methods known in the art.The soluble receptors or binding protein(s) are subjected to N-terminalsequencing to obtain information sufficient for database identification,if the soluble protein is known, or for cloning, if the soluble proteinis unknown.

Example 64 Determination of PRO317-Induced Cellular Response

The biological activity of PRO317 is measured, for example, by bindingof an PRO317 of the invention to an PRO317 receptor. A test compound isscreened as an antagonist for its ability to block binding of PRO317 tothe receptor. A test compound is screened as an agonist of the PRO317for its ability to bind an PRO317 receptor and influence the samephysiological events as PRO317 using, for example, the KIRA-ELISA assaydescribed by Sadick et al., Analytical Biochemistry. 235:207-214 (1996)in which activation of a receptor tyrosine kinase is monitored byimmuno-capture of the activated receptor and quantitation of the levelof ligand-induced phosphorylation. The assay may be adapted to monitorPRO317-induced receptor activation through the use of an PRO317receptor-specific antibody to capture the activated receptor. Thesetechniques are also applicable to other PRO polypeptides describedherein.

Example 65 Use of PRO224 for Screening Compounds

PRO224 is expressed in a cell stripped of membrane proteins and capableof expressing PRO224. Low density lipoproteins having a detectable labelare added to the cells and incubated for a sufficient time forendocytosis. The cells are washed. The cells are then analysed for labelbound to the membrane and within the cell after cell lysis. Detection ofthe low density lipoproteins within the cell determines that PRO224 iswithin the family of low density lipoprotein receptor proteins. Membersfound within this family are then used for screening compounds whichaffect these receptors, and particularly the uptake of cholesterol viathese receptors.

Example 66 Ability of PRO Polypeptides to Inhibit Vascular EndothelialGrowth Factor (VEGF) Stimulated Proliferation of Endothelial Cell Growth(Assay 9)

The ability of various PRO polypeptides to inhibit VEGF stimulatedproliferation of endothelial cells was tested. Polypeptides testingpositive in this assay are useful for inhibiting endothelial cell growthin mammals where such an effect would be beneficial, e.g., forinhibiting tumor growth.

Specifically, bovine adrenal cortical capillary endothelial cells (ACE)(from primary culture, maximum of 12-14 passages) were plated in 96-wellplates at 500 cells/well per 100 microliter. Assay media included lowglucose DMEM, 10% calf serum, 2 mM glutamine, and1×penicillin/streptomycin/fungizone. Control wells included thefollowing: (1) no ACE cells added; (2) ACE cells alone; (3) ACE cellsplus 5 ng/ml FGF; (4) ACE cells plus 3 ng/ml VEGF; (5) ACE cells plus 3ng/ml VEGF plus 1 ng/ml TGF-beta; and (6) ACE cells plus 3 ng/ml VEGFplus 5 ng/ml LIF. The test samples, poly-his tagged PRO polypeptides (in100 microliter volumes), were then added to the wells (at dilutions of1%, 0.1% and 0.01%, respectively). The cell cultures were incubated for6-7 days at 37° C./5% CO₂. After the incubation, the media in the wellswas aspirated, the cells were washed 1× with PBS. An acid phosphatasereaction mixture (100 microliter; 0.1M sodium acetate, pH 5.5, 0.1%Triton X-100, 10 mM p-nitrophenyl phosphate) was then added to eachwell. After a 2 hour incubation at 37° C., the reaction was stopped byaddition of 10 microliters 1N NaOH. Optical density (OD) was measured ona microplate reader at 405 nm.

The activity of PRO polypeptides was calculated as the percentinhibition of VEGF (3 ng/ml) stimulated proliferation (as determined bymeasuring acid phosphatase activity at OD 405 nm) relative to the cellswithout stimulation. TGF-beta was employed as an activity reference at 1ng/ml, since TGF-beta blocks 70-90% of VEGF-stimulated ACE cellproliferation. The results are indicative of the utility of the PROpolypeptides in cancer therapy and specifically in inhibiting tumorangiogenesis. Numerical values (relative inhibition) are determined bycalculating the percent inhibition of VEGF stimulated proliferation bythe PRO polypeptides relative to cells without stimulation and thendividing that percentage into the percent inhibition obtained by TGF-βat 1 ng/ml which is known to block 70-90% of VEGF stimulated cellproliferation. The results are considered positive if the PROpolypeptide exhibits 30% or greater inhibition of VEGF stimulation ofendothelial cell growth (relative inhibition 30% or greater).

The following polypeptides tested positive in this assay: PRO211,PRO217, PRO187, PRO219, PRO246, PRO228, PRO245, PRO221, PRO258, PRO301,PRO224, PRO272, PRO328, PRO331, PRO224, PRO328, PRO272, PRO301, PRO331and PRO214.

Example 67 Retinal Neuron Survival (Assay 52)

This example demonstrates that certain PRO polypeptides have efficacy inenhancing the survival of retinal neuron cells and, therefore, areuseful for the therapeutic treatment of retinal disorders or injuriesincluding, for example, treating sight loss in mammals due to retinitispigmentosum, AMD, etc.

Sprague Dawley rat pups at postnatal day 7 (mixed population: glia andretinal neuronal types) are killed by decapitation following CO₂anesthesia and the eyes are removed under sterile conditions. The neuralretina is dissected away from the pigment epithelium and other oculartissue and then dissociated into a single cell suspension using 0.25%trypsin in Ca²⁺, Mg²⁺-free PBS. The retinas are incubated at 37° C. for7-10 minutes after which the trypsin is inactivated by adding 1 mlsoybean trypsin inhibitor. The cells are plated at 100,000 cells perwell in 96 well plates in DMEM/F12 supplemented with N2 and with orwithout the specific test PRO polypeptide. Cells for all experiments aregrown at 37° C. in a water saturated atmosphere of 5% CO₂. After 2-3days in culture, cells are stained with calcein AM then fixed using 4%paraformaldehyde and stained with DAPI for determination of total cellcount. The total cells (fluorescent) are quantified at 20× objectivemagnification using CCD camera and NIH image software for MacIntosh.Fields in the well are chosen at random.

The effect of various concentration of PRO polypeptides are reportedherein where percent survival is calculated by dividing the total numberof calcein AM positive cells at 2-3 days in culture by the total numberof DAPI-labeled cells at 2-3 days in culture. Anything above 30%survival is considered positive.

The following PRO polypeptides tested positive in this assay usingpolypeptide concentrations within the range of 0.01% to 1.0% in theassay: PRO220 and PRO346.

Example 68 Rod Photoreceptor Cell Survival (Assay 56)

This assay shows that certain polypeptides of the invention act toenhance the survival/proliferation of rod photoreceptor cells and,therefore, are useful for the therapeutic treatment of retinal disordersor injuries including, for example, treating sight loss in mammals dueto retinitis pigmentosum, AMD, etc. Sprague Dawley rat pups at 7 daypostnatal (mixed population: glia and retinal neuronal cell types) arekilled by decapitation following CO₂ anesthesis and the eyes are removedunder sterile conditions. The neural retina is dissected away form thepigment epithelium and other ocular tissue and then dissociated into asingle cell suspension using 0.25% trypsin in Ca²⁺, Mg²⁺-free PBS. Theretinas are incubated at 37° C. for 7-10 minutes after which the trypsinis inactivated by adding 1 ml soybean trypsin inhibitor. The cells areplated at 100,000 cells per well in 96 well plates in DMEM/F12supplemented with N₂. Cells for all experiments are grown at 37° C. in awater saturated atmosphere of 5% CO₂. After 2-3 days in culture, cellsare fixed using 4% paraformaldehyde, and then stained using CellTrackerGreen CMFDA. Rho 4D2 (ascites or IgG 1:100), a monoclonal antibodydirected towards the visual pigment rhodopsin is used to detect rodphotoreceptor cells by indirect immunofluorescence. The results arecalculated as % survival: total number of calcein−rhodopsin positivecells at 2-3 days in culture, divided by the total number of rhodopsinpositive cells at time 2-3 days in culture. The total cells(fluorescent) are quantified at 20× objective magnification using a CCDcamera and NIH image software for MacIntosh. Fields in the well arechosen at random.

The following polypeptides tested positive in this assay: PRO220 andPRO346.

Example 69 Induction of Endothelial Cell Apoptosis (Assay 73)

The ability of PRO polypeptides to induce apoptosis in endothelial cellswas tested in human venous umbilical vein endothelial cells (HUVEC, CellSystems). A positive test in the assay is indicative of the usefulnessof the polypeptide in therapeutically treating tumors as well asvascular disorders where inducing apoptosis of endothelial cells wouldbe beneficial.

The cells were plated on 96-well microtiter plates (Amersham LifeScience, cytostar-T scintillating microplate, RPNQ160, sterile,tissue-culture treated, individually wrapped), in 10% serum (CSG-medium,Cell Systems), at a density of 2×10⁴ cells per well in a total volume of100 μl. On day 2, test samples containing the PRO polypeptide were addedin triplicate at dilutions of 1%, 0.33% and 0. 11%. Wells without cellswere used as a blank and wells with cells only were used as a negativecontrol. As a positive control 1:3 serial dilutions of 50 μl of a 3×stock of staurosporine were used. The ability of the PRO polypeptide toinduce apoptosis was determined by processing of the 96 well plates fordetection of Annexin V, a member of the calcium and phospholipid bindingproteins, to detect apoptosis.

0.2 ml Annexin V-Biotin stock solution (100 μg/ml) was diluted in 4.6 ml2×Ca²⁺ binding buffer and 2.5% BSA (1:25 dilution). 50 μl of the dilutedAnnexin V-Biotin solution was added to each well (except controls) to afinal concentration of 1.0 μg/ml. The samples were incubated for 10-15minutes with Annexin-Biotin prior to direct addition of³⁵S-Streptavidin. ³⁵S-Streptavidin was diluted in 2×Ca²⁺ Binding buffer,2.5% BSA and was added to all wells at a final concentration of 3×10⁴cpm/well. The plates were then sealed, centrifuged at 1000 rpm for 15minutes and placed on orbital shaker for 2 hours. The analysis wasperformed on a 1450 Microbeta Trilux (Wallac). Percent above backgroundrepresents the percentage amount of counts per minute above the negativecontrols. Percents greater than or equal to 30% above background areconsidered positive.

The following PRO polypeptides tested positive in this assay: PRO228,PRO217 and PRO301.

Example 70 PDB12 Cell Inhibition (Assay 40)

This example demonstrates that various PRO polypeptides have efficacy ininhibiting protein production by PDB12 pancreatic ductal cells and are,therefore, useful in the therapeutic treatment of disorders whichinvolve protein secretion by the pancreas, including diabetes, and thelike.

PDB12 pancreatic ductal cells are plated on fibronectin coated 96 wellplates at 1.5×10³ cells per well in 100 μL/180 μL of growth media. 100μL of growth media with the PRO polypeptide test sample or negativecontrol lacking the PRO polypeptide is then added to well, for a finalvolume of 200 μL. Controls contain growth medium containing a proteinshown to be inactive in this assay. Cells are incubated for 4 days at37° C. 20 μL of Alamar Blue Dye (AB) is then added to each well and theflourescent reading is measured at 4 hours post addition of AB, on amicrotiter plate reader at 530 nm excitation and 590 nm emission. Thestandard employed is cells without Bovine Pituitary Extract (BPE) andwith various concentrations of BPE. Buffer or CM controls from unknownsare run 2 times on each 96 well plate.

These assays allow one to calculate a percent decrease in proteinproduction by comparing the Alamar Blue Dye calculated proteinconcentration produced by the PRO polypeptide-treated cells with theAlamar Blue Dye calculated protein concentration produced by thenegative control cells. A percent decrease in protein production ofgreater than or equal to 25% as compared to the negative control cellsis considered positive.

The following polypeptides tested positive in this assay: PRO211,PRO287, PRO301 and PRO293.

Example 71 Stimulation of Adult Heart Hypertrophy (Assay 2)

This assay is designed to measure the ability of various PROpolypeptides to stimulate hypertrophy of adult heart. PRO polypeptidestesting positive in this assay would be expected to be useful for thetherapeutic treatment of various cardiac insufficiency disorders.

Ventricular myocytes freshly isolated from adult (250 g) Sprague Dawleyrats are plated at 2000 cell/well in 180 μL volume. Cells are isolatedand plated on day 1, the PRO polypeptide-containing test samples orgrowth medium only (negative control) (20 μl volume) is added on day 2and the cells are then fixed and stained on day 5. After staining, cellsize is visualized wherein cells showing no growth enhancement ascompared to control cells are given a value of 0.0, cells showing smallto moderate growth enhancement as compared to control cells are given avalue of 1.0 and cells showing large growth enhancement as compared tocontrol cells are given a value of 2.0. Any degree of growth enhancementas compared to the negative control cells is considered positive for theassay.

The following PRO polypeptides tested positive in this assay: PRO287,PRO301, PRO293 and PRO303.

Example 72 PDB12 Cell Proliferation (Assay 29)

This example demonstrates that various PRO polypeptides have efficacy ininducing proliferation of PDB12 pancreatic ductal cells and are,therefore, useful in the therapeutic treatment of disorders whichinvolve protein secretion by the pancreas, including diabetes, and thelike.

PDB12 pancreatic ductal cells are plated on fibronectin coated 96 wellplates at 1.5×10³ cells per well in 100 μL/180 μL of growth media. 100μL of growth media with the PRO polypeptide test sample or negativecontrol lacking the PRO polypeptide is then added to well, for a finalvolume of 200 μL. Controls contain growth medium containing a proteinshown to be inactive in this assay. Cells are incubated for 4 days at37° C. 20 μL of Alamar Blue Dye (AB) is then added to each well and theflourescent reading is measured at 4 hours post addition of AB, on amicrotiter plate reader at 530 nm excitation and 590 nm emission. Thestandard employed is cells without Bovine Pituitary Extract (BPE) andwith various concentrations of BPE. Buffer or growth medium onlycontrols from unknowns are run 2 times on each 96 well plate.

Percent increase in protein production is calculated by comparing theAlamar Blue Dye calculated protein concentration produced by the PROpolypeptide-treated cells with the Alamar Blue Dye calculated proteinconcentration produced by the negative control cells. A percent increasein protein production of greater than or equal to 25% as compared to thenegative control cells is considered positive.

The following PRO polypeptides tested positive in this assay: PRO301 andPRO303.

Example 73 Enhancement of Heart Neonatal Hypertrophy (Assay 1)

This assay is designed to measure the ability of PRO polypeptides tostimulate hypertrophy of neonatal heart. PRO polypeptides testingpositive in this assay are expected to be useful for the therapeutictreatment of various cardiac insufficiency disorders.

Cardiac myocytes from 1-day old Harlan Sprague Dawley rats wereobtained. Cells (180 μL at 7.5×10⁴/ml, serum <0.1%, freshly isolated)are added on day 1 to 96-well plates previously coated with DMEM/F12+4%FCS. Test samples containing the test PRO polypeptide or growth mediumonly (hegative control) (20 μl/well) are added directly to the wells onday 1. PGF (20 μl/well) is then added on day 2 at final concentration of10⁻⁶ M. The cells are then stained on day 4 and visually scored on day5, wherein cells showing no increase in size as compared to negativecontrols are scored 0.0, cells showing a small to moderate increase insize as compared to negative controls are scored 1.0 and cells showing alarge increase in size as compared to negative controls are scored 2.0.A positive result in the assay is a score of 1.0 or greater.

The following polypeptides tested positive in this assay: PRO224 andPRO231.

Example 74 Stimulatory Activity in Mixed Lymphocyte Reaction (MLR) Assay(Assay 24)

This example shows that certain polypeptides of the invention are activeas a stimulator of the proliferation of stimulated T-lymphocytes.Compounds which stimulate proliferation of lymphocytes are usefultherapeutically where enhancement of an immune response is beneficial. Atherapeutic agent may take the form of antagonists of the polypeptide ofthe invention, for example, murine-human chimeric, humanized or humanantibodies against the polypeptide.

The basic protocol for this assay is described in Current Protocols inImmunology, unit 3.12; edited by J E Coligan, A M Kruisbeek, D HMarglies, E M Shevach, W Strober, National Insitutes of Health,Published by John Wiley & Sons, Inc.

More specifically, in one assay variant, peripheral blood mononuclearcells (PBMC) are isolated from mammalian individuals, for example ahuman volunteer, by leukopheresis (one donor will supply stimulatorPBMCs, the other donor will supply responder PBMCs). If desired, thecells are frozen in fetal bovine serum and DMSO after isolation. Frozencells may be thawed overnight in assay media (37° C., 5% CO₂) and thenwashed and resuspended to 3×10⁶ cells/ml of assay media (RPMI; 10% fetalbovine serum, 1% penicillin/streptomycin, 1% glutamine, 1% HEPES, 1%non-essential amino acids, 1% pyruvate). The stimulator PBMCs areprepared by irradiating the cells (about 3000 Rads).

The assay is prepared by plating in triplicate wells a mixture of:

100:1 of test sample diluted to 1% or to 0.1%,

50:1 of irradiated stimulator cells, and

50:1 of responder PBMC cells.

100 microliters of cell culture media or 100 microliter of CD4-IgG isused as the control. The wells are then incubated at 37° C., 5% CO₂ for4 days. On day 5, each well is pulsed with tritiated thymidine (1.0mC/well; Amersham). After 6 hours the cells are washed 3 times and thenthe uptake of the label is evaluated.

In another variant of this assay, PBMCs are isolated from the spleens ofBalb/c mice and C57B6 mice. The cells are teased from freshly harvestedspleens in assay media (RPMI; 10% fetal bovine serum, 1%penicillin/streptomycin, 1% glutamine, 1% HEPES, 1% non-essential aminoacids, 1% pyruvate) and the PBMCs are isolated by overlaying these cellsover Lympholyte M (Organon Teknika), centrifuging at 2000 rpm for 20minutes, collecting and washing the mononuclear cell layer in assaymedia and resuspending the cells to 1×10⁷ cells/ml of assay media. Theassay is then conducted as described above.

Positive increases over control are considered positive with increasesof greater than or equal to 180% being preferred. However, any valuegreater than control indicates a stimulatory effect for the testprotein.

The following PRO polypeptides tested positive in this assay: PRO245,PRO269, PRO217, PRO301, PRO266, PRO335, PRO331, PRO533 and PRO326.

Example 75 Pericyte c-Fos Induction (Assay 93)

This assay shows that certain polypeptides of the invention act toinduce the expression of c-fos in pericyte cells and, therefore, areuseful not only as diagnostic markers for particular types ofpericyte-associated tumors but also for giving rise to antagonists whichwould be expected to be useful for the therapeutic treatment ofpericyte-associated tumors. Specifically, on day 1, pericytes arereceived from VEC Technologies and all but 5 ml of media is removed fromflask. On day 2, the pericytes are trypsinized, washed, spun and thenplated onto 96 well plates. On day 7, the media is removed and thepericytes are treated with 100 μl of PRO polypeptide test samples andcontrols (positive control=DME+5% serum +/−PDGF at 500 ng/ml; negativecontrol=protein 32). Replicates are averaged and SD/CV are determined.Fold increase over Protein 32 (buffer control) value indicated bychemiluminescence units (RLU) lumninometer reading verses frequency isplotted on a histogram. Two-fold above Protein 32 value is consideredpositive for the assay. ASY Matrix: Growth media=low glucose DMEM=20%FBS+1×pen strep+1×fungizone. Assay Media=low glucose DMEM+5% FBS.

The following polypeptides tested positive in this assay: PRO214,PRO219, PRO221 and PRO224.

Example 76 Ability of PRO Polypeptides to Stimulate the Release ofProteoglycans from Cartilage (Assay 97)

The ability of various PRO polypeptides to stimulate the release ofproteoglycans from cartilage tissue was tested as follows.

The metacarphophalangeal joint of 4-6 month old pigs was asepticallydissected, and articular cartilage was removed by free hand slicingbeing careful to avoid the underlying bone. The cartilage was minced andcultured in bulk for 24 hours in a humidified atmosphere of 95% air, 5%CO₂ in serum free (SF) media (DME/F121:1) woth 0.1% BSA and 100 U/mlpenicillin and 100 μg/ml streptomycin. After washing three times,approximately 100 mg of articular cartilage was aliquoted into micronicstubes and incubated for an additional 24 hours in the above SF media.PRO polypeptides were then added at 1% either alone or in combinationwith 18 ng/ml interleukin-1α, a known stimulator of proteoglycan releasefrom cartilage tissue. The supernatant was then harvested and assayedfor the amount of proteoglycans using the 1,9-dimethyl-methylene blue(DMB) colorimetric assay (Farndale and Buttle, Biochem. Biophys. Acta883:173-177 (1985)). A positive result in this assay indicates that thetest polypeptide will find use, for example, in the treatment ofsports-related joint problems, articular cartilage defects,osteoarthritis or rheumatoid arthritis.

When various PRO polypeptides were tested in the above assay, thepolypeptides demonstrated a marked ability to stimulate release ofproteoglycans from cartilage tissue both basally and after stimulationwith interleukin-1α and at 24 and 72 hours after treatment, therebyindicating that these PRO polypeptides are useful for stimulatingproteoglycan release from cartilage tissue. As such, these PROpolypeptides are useful for the treatment of sports-related jointproblems, articular cartilage defects, osteoarthritis or rheumatoidarthritis. The polypeptides testing positive in this assay are: PRO211.

Example 77 Skin Vascular Permeability Assay (Assay 64)

This assay shows that certain polypeptides of the invention stimulate animmune response and induce inflammation by inducing mononuclear cell,eosinophil and PMN infiltration at the site of injection of the animal.Compounds which stimulate an immune response are useful therapeuticallywhere stimulation of an immune response is beneficial. This skinvascular permeability assay is conducted as follows. Hairless guineapigs weighing 350 grams or more are anesthetized with ketamine (75-80mg/Kg) and 5 mg/Kg xylazine intramuscularly (IM). A sample of purifiedpolypeptide of the invention or a conditioned media test sample isinjected intradermally onto the backs of the test animals with 100 μlper injection site. It is possible to have about 10-30, preferably about16-24, injection sites per animal. One μl of Evans blue dye (1% inphysiologic buffered saline) is injected intracardially. Blemishes atthe injection sites are then measured (mm diameter) at 1 hr and 6 hrpost injection. Animals were sacrificed at 6 hrs after injection. Eachskin injection site is biopsied and fixed in formalin. The skins arethen prepared for histopathologic evaluation. Each site is evaluated forinflammatory cell infiltration into the skin. Sites with visibleinflammatory cell inflammation are scored as positive. Inflammatorycells may be neutrophilic, eosinophilic, monocytic or lymphocytic. Atleast a minimal perivascular infiltrate at the injection site is scoredas positve, no infiltrate at the site of injection is scored asnegative.

The following polypeptides tested positive in this assay: PRO245,PRO217, PRO326, PRO266, PRO272, PRO301, PRO331 and PRO335.

Example 78 Enhancement of Heart Neonatal Hypertrophy Induced by F2a(Assay 37)

This assay is designed to measure the ability of PRO polypeptides tostimulate hypertrophy of neonatal heart. PRO polypeptides testingpositive in this assay are expected to be useful for the therapeutictreatment of various cardiac insufficiency disorders.

Cardiac myocytes from 1-day old Harlan Sprague Dawley rats wereobtained. Cells (180 μl at 7.5×10⁴/ml, serum<0.1%, freshly isolated) areadded on day 1 to 96-well plates previously coated with DMEM/F12+4% FCS.Test samples containing the test PRO polypeptide (20 μl/well) are addeddirectly to the wells on day 1. PGF (20 μl/well) is then added on day 2at a final concentration of 10⁻⁶ M. The cells are then stained on day 4and visually scored on day 5. Visual scores are based on cell size,wherein cells showing no increase in size as compared to negativecontrols are scored 0.0, cells showing a small to moderate increase insize as compared to negative controls are scored 1.0 and cells showing alarge increase in size as compared to negative controls are scored 2.0.A score of 1.0 or greater is considered positive.

No PBS is included, since calcium concentration is critical for assayresponse. Plates are coated with DMEM/F12 plus 4% FCS (200 μl/well).Assay media included: DMEM/F12 (with 2.44 gm bicarbonate), 10 μg/mltransferrin, 1 μg/ml insulin, 1 μg/ml aprotinin, 2 mmol/L glutamine, 100U/ml penicillin G, 100 μg/ml streptomycin. Protein buffer containingmannitol (4%) gave a positive signal (score 3.5) at 1/10 (0.4%) and1/100 (0.04%), but not at 1/1000 (0.004%). Therefore the test samplebuffer containing mannitol is not run.

The following PRO polypeptides tested positive in this assay: PRO224.

Example 79 Inhibitory Activity in Mixed Lymphocyte Reaction (MLR) Assay(Assay 67)

This example shows that one or more of the polypeptides of the inventionare active as inhibitors of the proliferation of stimulatedT-lymphocytes. Compounds which inhibit proliferation of lymphocytes areuseful therapeutically where suppression of an immune response isbeneficial.

The basic protocol for this assay is described in Current Protocols inImmunology, unit 3.12; edited by J E Coligan, A M Kruisbeek, D HMarglies, E M Shevach, W Strober, National Insitutes of Health,Published by John Wiley & Sons, Inc.

More specifically, in one assay variant, peripheral blood mononuclearcells (PBMC) are isolated from mammalian individuals, for example ahuman volunteer, by leukopheresis (one donor will supply stimulatorPBMCs, the other donor will supply responder PBMCs). If desired, thecells are frozen in fetal bovine serum and DMSO after isolation. Frozencells may be thawed overnight in assay media (37° C., 5% CO₂) and thenwashed and resuspended to 3×10⁶ cells/ml of assay media (RPMI; 10% fetalbovine serum, 1% penicillin/streptomycin, 1% glutamine, 1% HEPES, 1%non-essential amino acids, 1% pyruvate). The stimulator PBMCs areprepared by irradiating the cells (about 3000 Rads).

The assay is prepared by plating in triplicate wells a mixture of:

100:1 of test sample diluted to 1% or to 0.1%,

50:1 of irradiated stimulator cells, and

50:1 of responder PBMC cells. 100 microliters of cell culture media or100 microliter of CD4-IgG is used as the control. The wells are thenincubated at 37° C., 5% CO₂ for 4 days. On day 5, each well is pulsedwith tritiated thymidine (1.0 mC/well; Amersham). After 6 hours thecells are washed 3 times and then the uptake of the label is evaluated.

In another variant of this assay, PBMCs are isolated from the spleens ofBalb/c mice and C57B6 mice. The cells are teased from freshly harvestedspleens in assay media (RPMI; 10% fetal bovine serum, 1%penicillin/streptomycin, 1% glutamine, 1% HEPES, 1% non-essential aminoacids, 1% pyruvate) and the PBMCs are isolated by overlaying these cellsover Lympholyte M (Organon Teknika), centrifuging at 2000 rpm for 20minutes, collecting and washing the mononuclear cell layer in assaymedia and resuspending the cells to 1×10⁷ cells/ml of assay media. Theassay is then conducted as described above.

Any decreases below control is considered to be a positive result for aninhibitory compound, with decreases of less than or equal to 80% beingpreferred. However, any value less than control indicates an inhibitoryeffect for the test protein.

The following polypeptide tested positive in this assay: PRO235, PRO245and PRO332.

Example 80 Induction of Endothelial Cell Aportosis (ELISA) (Assay 109)

The ability of PRO polypeptides to induce apoptosis in endothelial cellswas tested in human venous umbilical vein endothelial cells (HUVEC, CellSystems) using a 96-well format, in 0% serum media supplemented with 100ng/ml VEGF, 0.1% BSA, 1×penn/strep. A positive result in this assayindicates the usefulness of the polypeptide for therapeutically treatingany of a variety of conditions associated with undesired endothelialcell growth including, for example, the inhibition of tumor growth. The96-well plates used were manufactured by Falcon (No. 3072). Coating of96 well plates were prepared by allowing gelatinization to occur for >30minutes with 100 μl of 0.2% gelatin in PBS solution. The gelatin mix wasaspirated thoroughly before plating HUVEC cells at a final concentrationof 2×10⁴ cells/ml in 10% serum containing medium −100 μl volume perwell. The cells were grown for 24 hours before adding test samplescontaining the PRO polypeptide of interest.

To all wells, 100 μl of 0% serum media (Cell Systems) complemented with100 ng/ml VEGF, 0.1% BSA, 1×penn/strep was added. Test samplescontaining PRO polypeptides were added in triplicate at dilutions of 1%,0.33% and 0.11%. Wells without cells were used as a blank and wells withcells only were used as a negative control. As a positive control, 1:3serial dilutions of 50 μl of a 3× stock of staurosporine were used. Thecells were incubated for 24 to 35 hours prior to ELISA.

ELISA was used to determine levels of apoptosis preparing solutionsaccording to the Boehringer Manual [Boehringer, Cell Death DetectionELISA plus, Cat No. 1 920 685]. Sample preparations: 96 well plates werespun down at 1 krpm for 10 minutes (200 g); the supernatant was removedby fast inversion, placing the plate upside down on a paper towel toremove residual liquid. To each well, 200 μl of 1×Lysis buffer was addedand incubation allowed at room temperature for 30 minutes withoutshaking. The plates were spun down for 10 minutes at 1 krpm, and 20 μlof the lysate (cytoplasmic fraction) was transferred into streptavidincoated MTP. 80 μl of immunoreagent mix was added to the 20 μl lystate ineach well. The MTP was covered with adhesive foil and incubated at roomtempearature for 2 hours by placing it on an orbital shaker (200 rpm).After two hours, the supernatant was removed by suction and the wellsrinsed three times with 250 μl of 1× incubation buffer per well (removedby suction). Substrate solution was added (100 μl) into each well andincubated on an orbital shaker at room temperature at 250 rpm untilcolor development was sufficient for a photometric analysis (approx.after 10-20 minutes). A 96 well reader was used to read the plates at405 nm, reference wavelength, 492 nm. The levels obtained for PIN 32(control buffer) was set to 100%. Samples with levels>130% wereconsidered positive for induction of apoptosis.

The following PRO polypeptides tested positive in this assay: PRO235.

Example 81 Human Venous Endothelial Cell Calcium Flux Assay (Assay 68)

This assay is designed to determine whether PRO polypeptides of thepresent invention show the ability to stimulate calcium flux in humanumbilical vein endothelial cells (HUVEC, Cell Systems). Calcium influxis a well documented response upon binding of certain ligands to theirreceptors. A test compound that results in a positive response in thepresent calcium influx assay can be said to bind to a specific receptorand activate a biological signaling pathway in human endothelial cells.This could ultimately lead, for example, to endothelial cell division,inhibition of endothelial cell proliferation, endothelial tubeformation, cell migration, apoptosis, etc.

Human venous umbilical vein endothelial cells (HUVEC, Cell Systems) ingrowth media (50:50 without glycine, 1% glutamine, 10 mM Hepes, 10% FBS,10 ng/ml bFGF), were plated on 96-well microtiter ViewPlates-96 (PackardInstrument Company Part #6005182) microtiter plates at a cell density of2×10⁴ cells/well. The day after plating, the cells were washed threetimes with buffer (HBSS plus 10 mM Hepes), leaving 100 μl/well. Then 100μl/well of 8 μM Fluo-3 (2×) was added. The cells were incubated for 1.5hours at 37° C./5% CO₂. After incubation, the cells were then washed 3×with buffer (described above) leaving 100 μl/well. Test samples of thePRO polypeptides were prepared on different 96-well plates at 5×concentration in buffer. The positive control corresponded to 50 μMionomycin (5×); the negative control corresponded to Protein 32. Cellplate and sample plates were run on a FLIPR (Molecular Devices) machine.The FLIPR machine added 25 μl of test sample to the cells, and readingswere taken every second for one minute, then every 3 seconds for thenext three minutes.

The fluorescence change from baseline to the maximum rise of the curve(Δ change) was calculated, and replicates averaged. The rate offluorescence increase was monitored, and only those samples which had aΔ change greater than 1000 and a rise within 60 seconds, were consideredpositive.

The following PRO polypeptides tested positive in the present assay:PRO245.

Example 82 Fibroblast (BHK-21) Proliferation (Assay 98)

This assay shows that certain PRO polypeptides of the invention act toinduce proliferation of mammalian fibroblast cells in culture and,therefore, function as useful growth factors in mammalian systems. Theassay is performed as follows. BHK-21 fibroblast cells plated instandard growth medium at 2500 cells/well in a total volume of 100 μl.The PRO polypeptide, β-FGF (positive control) or nothing (negativecontrol) are then added to the wells in the presence of 1 μg/ml ofheparin for a total final volume of 200 μl. The cells are then incubatedat 37° C. for 6 to 7 days. After incubation, the media is removed, thecells are washed with PBS and then an acid phosphatase substratereaction mixture (100 μl/well) is added. The cells are then incubated at37° C. for 2 hours. 10 μl per well of 1N NaOH is then added to stop theacid phosphatase reaction. The plates are then read at OD 405 nm. Apositive in the assay is acid phosphatase activity which is at least 50%above the negative control.

The following PRO polypeptide tested positive in this assay: PRO258.

Example 83 Inhibition of Heart Adult Hypertrophy (Assay 42)

This assay is designed to measure the inhibition of heart adulthypertrophy. PRO polypeptides testing positive in this assay may finduse in the therapeutic treatment of cardiac disorders associated withcardiac hypertrophy.

Ventricular myocytes are freshly isolated from adult (250 g) HarlanSprague Dawley rats and the cells are plated at 2000/well in 180 μlvolume. On day two, test samples (20 μl) containing the test PROpolypeptide are added. On day five, the cells are fixed and thenstained. An increase in ANP message can also be measured by PCR fromcells after a few hours. Results are based on a visual score of cellsize: 0=no inhibition, −1=small inhibition, −2=large inhibition. A scoreof less than 0 is considered positive. Activity reference corresponds tophenylephrin (PE) at 0.1 mM, as a positive control. Assay mediaincluded: M199 (modified)-glutamine free, NaHCO₃, phenol red,supplemented with 100 nM insulin, 0.2% BSA, 5 mM cretine, 2 mML-carnitine, 5 mM taurine, 100 U/ml penicillin G, 100 μg/ml streptomycin(CCT medium). Only inner 60 wells are used in 96 well plates. Of these,6 wells are reserved for negative and positive (PE) controls.

The following PRO polypeptides provided a score of less than 0 in theabove assay: PRO269.

Example 84 Induction of c-fos in Endothelial Cells (Assay 34)

This assay is designed to determine whether PRO polypeptides show theability to induce c-fos in endothelial cells. PRO polypeptides testingpositive in this assay would be expected to be useful for thetherapeutic treatment of conditions or disorders where angiogenesiswould be beneficial including, for example, wound healing, and the like(as would agonists of these PRO polypeptides). Antagonists of the PROpolypeptides testing positive in this assay would be expected to beuseful for the therapeutic treatment of cancerous tumors.

Human venous umbilical vein endothelial cells (HUVEC, Cell Systems) ingrowth media (50% Ham's F12 w/o GHT: low glucose, and 50% DMEM withoutglycine: with NaHCO3, 1% glutamine, 10 mM HEPES, 10% FBS, 10 ng/ml bFGF)were plated on 96-well microtiter plates at a cell density of 1×10⁴cells/well. The day after plating, the cells were starved by removingthe growth media and treating the cells with 100 μl/well test samplesand controls (positive control=growth media; negative control=Protein 32buffer=10 mM HEPES, 140 mM NaCl, 4% (w/v) mannitol, pH 6.8). The cellswere incubated for 30 minutes at 37° C., in 5% CO₂. The samples wereremoved, and the first part of the bDNA kit protocol (ChironDiagnostics, cat. #6005-037) was followed, where each capitalizedreagent/buffer listed below was available from the kit.

Briefly, the amounts of the TM Lysis Buffer and Probes needed for thetests were calculated based on information provided by the manufacturer.The appropriate amounts of thawed Probes were added to the TM LysisBuffer. The Capture Hybridization Buffer was warmed to room temperature.The bDNA strips were set up in the metal strip holders, and 100 μl ofCapture Hybridization Buffer was added to each B-DNA well needed,followed by incubation for at least 30 minutes. The test plates with thecells were removed from the incubator, and the media was gently removedusing the vacuum manifold. 100 μl of Lysis Hybridization Buffer withProbes were quickly pipetted into each well of the microtiter plates.The plates were then incubated at 55° C. for 15 minutes. Upon removalfrom the incubator, the plates were placed on the vortex mixer with themicrotiter adapter head and vortexed on the #2 setting for one minute.80 μl of the lysate was removed and added to the bDNA wells containingthe Capture Hybridization Buffer, and pipetted up and down to mix. Theplates were incubated at 53° C. for at least 16 hours.

On the next day, the second part of the bDNA kit protocol was followed.Specifically, the plates were removed from the incubator and placed onthe bench to cool for 10 minutes. The volumes of additions needed werecalculated based upon information provided by the manufacturer. AnAmplifier Working Solution was prepared by making a 1:100 dilution ofthe Amplifier Concentrate (20 fm/μl) in AL Hybridization Buffer. Thehybridization mixture was removed from the plates and washed twice withWash A. 50 μl of Amplifier Working Solution was added to each well andthe wells were incubated at 53° C. for 30 minutes. The plates were thenremoved from the incubator and allowed to cool for 10 minutes. The LabelProbe Working Solution was prepared by making a 1:100 dilution of LabelConcentrate (40 pmoles/μl) in AL Hybridization Buffer. After the10-minute cool-down period, the amplifier hybridization mixture wasremoved and the plates were washed twice with Wash A. 50 μl of LabelProbe Working Solution was added to each well and the wells wereincubated at 53° C. for 15 minutes. After cooling for 10 minutes, theSubstrate was warmed to room temperature. Upon addition of 3 μl ofSubstrate Enhancer to each ml of Substrate needed for the assay, theplates were allowed to cool for 10 minutes, the label hybridizationmixture was removed, and the plates were washed twice with Wash A andthree times with Wash D. 50 μl of the Substrate Solution with Enhancerwas added to each well. The plates were incubated for 30 minutes at 37°C. and RLU was read in an appropriate lumninometer.

The replicates were averaged and the coefficient of variation wasdetermined. The measure of activity of the fold increase over thenegative control (Protein 32/HEPES buffer described above) value wasindicated by chemiluminescence units (RLU). The results are consideredpositive if the PRO polypeptide exhibits at least a two-fold value overthe negative buffer control. Negative control=1.00 RLU at 1.00%dilution. Positive control=8.39 RLU at 1.00% dilution.

The following PRO polypeptides tested positive in this assay: PRO287.

Example 85 Guinea Pig Vascular Leak (Assays 32 and 51)

This assay is designed to determine whether PRO polypeptides of thepresent invention show the ability to induce vascular permeability.Polypeptides testing positive in this assay are expected to be usefulfor the therapeutic treatment of conditions which would benefit fromenhanced vascular permeability including, for example, conditions whichmay benefit from enhanced local immune system cell infiltration.

Hairless guinea pigs weighing 350 grams or more were anesthetized withKetamine (75-80 mg/kg) and 5 mg/kg Xylazine intramuscularly. Testsamples containing the PRO polypeptide or a physiological buffer withoutthe test polypeptide are injected into skin on the back of the testanimals with 100 μl per injection site intradermally. There wereapproximately 16-24 injection sites per animal. One ml of Evans blue dye(1% in PBS) is then injected intracardially. Skin vascular permeabilityresponses to the compounds (i.e., blemishes at the injection sites ofinjection) are visually scored by measuring the diameter (in mm) ofblue-colored leaks from the site of injection at 1 and 6 hours postadministration of the test materials. The mm diameter of blueness at thesite of injection is observed and recorded as well as the severity ofthe vascular leakage. Blemishes of at least 5 mm in diameter areconsidered positive for the assay when testing purified proteins, beingindicative of the ability to induce vascular leakage or permeability. Aresponse greater than 7 mm diameter is considered positive forconditioned media samples. Human VEGF at 0.1 μg/100 μl is used as apositive control, inducing a response of 15-23 mm diameter.

The following PRO polypeptides tested positive in this assay: PRO302 andPRO533.

Example 86 Detection of Endothelial Cell Apoptosis (FACS) (Assay 96)

The ability of PRO polypeptides of the present invention to induceapoptosis in endothelial cells was tested in human venous umbilical veinendothelial cells (HUVEC, Cell Systems) in gelatinized T175 flasks usingHUVEC cells below passage 10. PRO polypeptides testing positive in thisassay are expected to be useful for therapeutically treating conditionswhere apoptosis of endothelial cells would be beneficial including, forexample, the therapeutic treatment of tumors.

On day one, the cells were split [420,000 cells per gelatinized 6 cmdishes—(11×10³cells/cm² Falcon Primaria)] and grown in media containingserum (CS-C, Cell System) overnight or for 16 hours to 24 hours.

On day 2, the cells were washed 1× with 5 ml PBS; 3 ml of 0% serummedium was added with VEGF (100 ng/ml); and 30 μl of the PRO testcompound (final dilution 1%) or 0% serum medium (negative control) wasadded. The mixtures were incubated for 48 hours before harvesting.

The cells were then harvested for FACS analysis. The medium wasaspirated and the cells washed once with PBS. 5 ml of 1×trypsin wasadded to the cells in a T-175 flask, and the cells were allowed to standuntil they were released from the plate (about 5-10 minutes).Trypsinization was stopped by adding 5 ml of growth media. The cellswere spun at 1000 rpm for 5 minutes at 4° C. The media was aspirated andthe cells were resuspended in 10 ml of 10% serum complemented medium(Cell Systems), 5 μl of Annexin-FITC (BioVison) added and chilled tubeswere submitted for FACS. A positive result was determined to be enhancedapoptosis in the PRO polypeptide treated samples as compared to thenegative control.

The following PRO polypeptides tested positive in this assay: PRO331.

Example 87 Induction of c-fos in Cortical Neurons (Assay 83)

This assay is designed to determine whether PRO polypeptides show theability to induce c-fos in cortical neurons. PRO polypeptides testingpositive in this assay would be expected to be useful for thetherapeutic treatment of nervous system disorders and injuries whereneuronal proliferation would be beneficial.

Cortical neurons are dissociated and plated in growth medium at 10,000cells per well in 96 well plates. After aproximately 2 cellulardivisions, the cells are treated for 30 minutes with the PRO polypeptideor nothing (negative control). The cells are then fixed for 5 minuteswith cold methanol and stained with an antibody directed againstphosphorylated CREB. mRNA levels are then calculated usingchemiluminescence. A positive in the assay is any factor that results inat least a 2-fold increase in c-fos message as compared to the negativecontrols.

The following PRO polypeptides tested positive in this assay: PRO229 andPRO269.

Example 88 Stimulation of Endothelial Tube Formation (Assay 85)

This assay is designed to determine whether PRO polypeptides show theability to promote endothelial vacuole and lumen formation in theabsence of exogenous growth factors. PRO polypeptides testing positivein this assay would be expected to be useful for the therapeutictreatment of disorders where endothelial vacuole and/or lumen formationwould be beneficial including, for example, where the stimulation ofpinocytosis, ion pumping, vascular permeability and/or junctionalformation would be beneficial.

HUVEC cells (passage<8 from primary) are mixed with type I rat tailcollagen (final concentration 2.6 mg/ml) at a density of 6×10⁵ cells perml and plated at 50 μl per well of M199 culture media supplement with 1%FBS and 1 μM 6-FAM-FITC dye to stain the vacuoles while they are formingand in the presence of the PRO polypeptide. The cells are then incubatedat 37° C./5% CO₂ for 48 hours, fixed with 3.7% formalin room temperaturefor 10 minutes, washed 5 times with M199 medium and then stained withRh-Phalloidin at 4° C. overnight followed by nuclear staining with 4 μMDAPI. A positive result in the assay is when vacuoles are present ingreater than 50% of the cells.

The following PRO polypeptides tested positive in this assay: PRO230.

Example 89 Detection of Polypeptides that Affect Glucose and/or FFAUntake in Skeletal Muscle (Assay 106)

This assay is designed to determine whether PRO polypeptides show theability to affect glucose or FFA uptake by skeletal muscle cells. PROpolypeptides testing positive in this assay would be expected to beuseful for the therapeutic treatment of disorders where either thestimulation or inhibition of glucose uptake by skeletal muscle would bebeneficial including, for example, diabetes or hyper- orhypo-insulinemia.

In a 96 well format, PRO polypeptides to be assayed are added to primaryrat differentiated skeletal muscle, and allowed to incubate overnight.Then fresh media with the PRO polypeptide and +/− insulin are added tothe wells. The sample media is then monitored to determine glucose andFFA uptake by the skeletal muscle cells. The insulin will stimulateglucose and FFA uptake by the skeletal muscle, and insulin in mediawithout the PRO polypeptide is used as a positive control, and a limitfor scoring. As the PRO polypeptide being tested may either stimulate orinhibit glucose and FFA uptake, results are scored as positive in theassay if greater than 1.5 times or less than 0.5 times the insulincontrol.

The following PRO polypeptides tested positive as either stimulators orinhibitors of glucose and/or FFA uptake in this assay: PRO187, PRO211,PRO221, PRO222, PRO224, PRO230, PRO239, PRO231, PRO245, PRO247, PRO258,PRO269, PRO328 and PRO533.

Example 90 Rod Photoreceptor Cell Survival Assay (Assay 46)

This assay shows that certain polypeptides of the invention act toenhance the survival/proliferation of rod photoreceptor cells and,therefore, are useful for the therapeutic treatment of retinal disordersor injuries including, for example, treating sight loss in mammals dueto retinitis pigmentosum, AMD, etc.

Sprague Dawley rat pups (postnatal day 7, mixed population: glia andnetinal neural cell types) are killed by decapitation following CO₂anesthesia and the eyes removed under sterile conditions. The neuralretina is dissected away from the pigment epithelium and other oculartissue and then dissociated into a single cell suspension using 0.25%trypsin in Ca²⁺, Mg²⁺-free PBS. The retinas are incubated at 37° C. inthis solution for 7-10 minutes after which the trypsin is inactivated byadding 1 ml soybean trypsin inhibitor. The cells are plated at a densityof approximately 10,000 cells/ml into 96 well plates in DMEM/F12supplemented with N₂. Cells for all experiments are grown at 37° C. in awater saturated atmosphere of 5% CO₂. After 7-10 days in culture, thecells are stained using calcein AM or CellTracker Green CMFDA and thenfixed using 4% paraformaldehyde. Rho 4D2 (ascities or IgG 1:100)monoclonal antibody directed towards the visual pigment rhodopsin isused to detect rod photoreceptor cells by indirect immunofluorescence.The results are calculated as % survival: total number ofcalcein—rhodopsin positive cells at 7-10 days in culture, divided by thetotal number of rhodopsin positive cells at time 7-10 days in culture.The total cells (fluorescent) are quantified at 20× objectivemagnification using a CCD camera and NIH image software for MacIntosh.Fields in the well are chosen at random.

The following polypeptides tested positive in this assay: PRO245.

Example 91 In Vitro Antitumor Assay (Assay 161)

The antiproliferative activity of various PRO polypeptides wasdetermined in the investigational, disease-oriented in vitro anti-cancerdrug discovery assay of the National Cancer Institute (NCI), using asulforhodamine B (SRB) dye binding assay essentially as described bySkehan et al., J. Natl. Cancer Inst. 82:1107-1112 (1990). The 60 tumorcell lines employed in this study (“the NCI panel”), as well asconditions for their maintenance and culture in vitro have beendescribed by Monks et al., J. Natl. Cancer Inst. 83:757-766 (1991). Thepurpose of this screen is to initially evaluate the cytotoxic and/orcytostatic activity of the test compounds against different types oftumors (Monks et al., supra; Boyd, Cancer: Princ. Pract. Oncol. Update3(10):1-12 [1989]).

Cells from approximately 60 human tumor cell lines were harvested withtrypsin/EDTA (Gibco), washed once, resuspended in IMEM and theirviability was determined. The cell suspensions were added by pipet (100μL volume) into separate 96-well microtiter plates. The cell density forthe 6-day incubation was less than for the 2-day incubation to preventovergrowth. Inoculates were allowed a preincubation period of 24 hoursat 37° C. for stabilization. Dilutions at twice the intended testconcentration were added at time zero in 100 μL aliquots to themicrotiter plate wells (1:2 dilution). Test compounds were evaluated atfive half-log dilutions (1000 to 100,000-fold). Incubations took placefor two days and six days in a 5% CO₂ atmosphere and 100% humidity.

After incubation, the medium was removed and the cells were fixed in 0.1ml of 10% trichloroacetic acid at 40° C. The plates were rinsed fivetimes with deionized water, dried, stained for 30 minutes with 0.1 ml of0.4% sulforhodamine B dye (Sigma) dissolved in 1% acetic acid, rinsedfour times with 1% acetic acid to remove unbound dye, dried, and thestain was extracted for five minutes with 0.1 ml of 10 mM Tris base[tris(hydroxymethyl)aminomethane], pH 10.5. The absorbance (OD) ofsulforhodamine B at 492 nm was measured using a computer-interfaced,96-well microtiter plate reader.

A test sample is considered positive if it shows at least 50% growthinhibitory effect at one or more concentrations. PRO polypeptidestesting positive in this assay are shown in Table 7, where theabbreviations are as follows:

NSCL=non-small cell lung carcinoma

CNS=central nervous system

TABLE 7 Test compound Tumor Cell Line Type Cell Line Designation PRO211NSCL HOP62 PRO211 Leukemia RPMI-8226 PRO211 Leukemia HL-60 (TB) PRO211NSCL NCI-H522 PRO211 CNS SF-539 PRO211 Melanoma LOX IMVI PRO211 BreastMDA-MB-435 PRO211 Leukemia MOLT-4 PRO211 CNS U251 PRO211 Breast MCF7PRO211 Leukemia HT-60 (TB) PRO211 Leukemia MOLT-4 PRO211 NSCL EKVXPRO211 NSCL NCI-H23 PRO211 NSCL NCI-H322M PRO211 NSCL NCI-H460 PRO211Colon HCT-116 PRO211 Colon HT29 PRO211 CNS SF-268 PRO211 CNS SF-295PRO211 CNS SNB-19 PRO211 CNS U251 PRO211 Melanoma LOX IMVI PRO211Melanoma SK-MEL-5 PRO211 Melanoma UACC-257 PRO211 Melanoma UACC-62PRO211 Ovarian OVCAR-8 PRO211 Renal RXF 393 PRO211 Breast MCF7 PRO211Breast NCI/ADR-REHS 578T PRO211 Breast T-47D PRO211 Leukemia HL-60 (TB)PRO211 Leukemia SR PRO211 NSCL NCI-H23 PRO211 Colon HCT-116 PRO211Melanoma LOX-IMVI PRO211 Melanoma SK-MEL-5 PRO211 Breast T-47D PRO228Leukemia MOLT-4 PRO228 NSCL EKVX PRO228 Colon KM12 PRO228 MelanomaUACC-62 PRO228 Ovarian OVCAR-3 PRO228 Renal TK10 PRO228 Renal SN12CPRO228 Breast MCF7 PRO228 Leukemia CCRF-CEM PRO228 Leukemia HL-60 (TB)PRO228 Colon COLO 205 PRO228 Colon HCT-15 PRO228 Colon KM12 PRO228 CNSSF-268 PRO228 CNS SNB-75 PRO228 Melanoma LOX-IMVI PRO228 MelanomaSK-MEL2 PRO228 Melanoma UACC-257 PRO228 Ovarian IGROV1 PRO228 OvarianOVCAR-4 PRO228 Ovarian OVCAR-5 PRO228 Ovarian OVCAR-8 PRO228 Renal 786-0PRO228 Renal CAXI-1 PRO228 Renal RXF 393 PRO228 Renal TK-10 PRO228 RenalUO-31 PRO228 Prostate PC-3 PRO228 Prostate DU-145 PRO228 Breast MCF7PRO228 Breast NCI/ADR-REHS 578T PRO228 Breast MDA-MB-435MDA-N PRO228Breast T-47D PRO219 Leukemia SR PRO219 NSCL NCI-H5222 PRO219 Breast MCF7PRO219 Leukemia K-562; RPMI-8226 PRO219 NSCL HOP-62; NCI-H322M PRO219NSCL NCI-H460 PRO219 Colon HT29; KM12; HCT-116 PRO219 CNS SF-539; U251PRO219 Prostate DU-145 PRO219 Breast MDA-N PRO219 Ovarian IGROV1 PRO219NSCL NCI-H226 PRO219 Leukemia MOLT-4 PRO219 NSCL A549/ATCC; EKVX;NCI-H23 PRO219 Colon HCC-2998 PRO219 CNS SF-295; SNB-19 PRO219 MelanomaSK-MEL-2; SK-MEL-5 PRO219 Melanoma UACC-257; UACC-62 PRO219 OvarianOCAR-4; SK-OV-3 PRO219 Renal 786-0; ACHN; CAKI-1; SN12C PRO219 RenalTK-10; UO-31 PRO219 Breast NCI/ADR-RES; BT-549; T-47D PRO219 BreastMDA-MB-435 PRO221 Leukemia CCRF-CEM PRO221 Leukemia MOLT-4 PRO221 NSCLHOP-62 PRO221 Breast MDA-N PRO221 Leukemia RPMI-8226; SR PRO221 NSCLNCI-H460 PRO221 Colon HCC-2998 PRO221 Ovarian IGROV1 PRO221 Renal TK-10PRO221 Breast MCF7 PRO221 Leukemia K-562 PRO221 Breast MDA-MB-435 PRO224Ovarian OVCAR-4 PRO224 Renal RXF 393 PRO224 Prostate DU-145 PRO224 NSCLHOP-62; NCJ-H322M PRO224 Melanoma LOX IMVI PRO224 Ovarian OVCAR-8 PRO224Leukemia SR PRO224 NSCL NCI-H460 PRO224 CNS SF-295 PRO224 LeukemiaRPMI-8226 PRO224 Breast BT-549 PRO224 Leukemia CCRF-CEM; LH-60 (TB)PRO224 Colon HCT-116 PRO224 Breast MDA-MB-435 PRO224 Leukemia HL-60 (TB)PRO224 Colon HCC-2998 PRO224 Prostate PC-3 PRO224 CNS U251 PRO224 ColonHCT-15 PRO224 CNS SF-539 PRO224 Renal ACHN PRO328 Leukemia RPMI-8226PRO328 NSCL A549/ATCC; EKVX; HOP-62 PRO328 NSCL NCI-H23; NCI-H322MPRO328 Colon HCT-15; KM12 PRO328 CNS SF-295; SF-539; SNB-19; U251 PRO328Melanoma M14; UACC-257; UCAA-62 PRO328 Renal 786-0; ACHN PRO328 BreastMCF7 PRO328 Leukemia SR PRO328 Colon NCI-H23 PRO328 Melanoma SK-MEL-5PRO328 Prostate DU-145 PRO328 Melanoma LOX IMVI PRO328 Breast MDA-MB-435PRO328 Ovarian OVCAR-3 PRO328 Breast T-47D PRO301 NSCL NCI-H322M PRO301Leukemia MOLT-4; SR PRO301 NSCL A549/ATCC; EKVX; PRO301 NSCL NCI-H23;NCI-460; NCI-H226 PRO301 Colon COLO 205; HCC-2998; PRO301 Colon HCT-15;KM12; HT29; PRO301 Colon HCT-116 PRO301 CNS SF-268; SF-295; SNB-19PRO301 Melanoma MALME-3M; SK-MEL-2; PRO301 Melanoma SK-MEL-5;UACC-257PRO301 Melanoma UACC-62 PRO301 Ovarian IGROV1; OVCAR-4 PRO301 OvarianOVCAR-5 PRO301 Ovarian OVCAR-8; SK0OV-3 PRO301 Renal ACHN;CAKI-1; TK-10;UO-31 PRO301 Prostate PC-3; DU-145 PRO301 Breast NCI/ADR-RES; HS 578TPRO301 Breast MDA-MB-435;MDA-N; T-47D PRO301 Melanoma M14 PRO301Leukemia CCRF-CEM;HL-60(TB); K-562 PRO301 Leukemia RPMI-8226 PRO301Melanoma LOX IMVI PRO301 Renal 786-0; SNI2C PRO301 Breast MCF7;MDA-MB-231/ATCC PRO301 Breast BT-549 PRO301 NSCL HOP-62 PRO301 CNSSF-539 PRO301 Ovarian OVCAR-3 PRO326 NSCL NCI-H322M PRO326 CNS SF295PRO326 CNS ST539 PRO326 CNS U251

The results of these assays demonstrate that the positive testing PROpolypeptides are useful for inhibiting neoplastic growth in a number ofdifferent tumor cell types and may be used therapeutically therefor.Antibodies against these PRO polypeptides are useful for affinitypurification of these useful polypeptides. Nucleic acids encoding thesePRO polypeptides are useful for the recombinant preparation of thesepolypeptides.

Example 92 Gene Amplification

This example shows that certain PRO polypeptide-encoding genes areamplified in the genome of certain human lung, colon and/or breastcancers and/or cell lines. Amplification is associated withoverexpression of the gene product, indicating that the polypeptides areuseful targets for therapeutic intervention in certain cancers such ascolon, lung, breast and other cancers and diagnostic determination ofthe presence of those cancers. Therapeutic agents may take the form ofantagonists of the PRO polypeptide, for example, murine-human chimeric,humanized or human antibodies against a PRO polypeptide.

The starting material for the screen was genomic DNA isolated from avariety cancers. The DNA is quantitated precisely, e.g.,fluorometrically. As a negative control, DNA was isolated from the cellsof ten normal healthy individuals which was pooled and used as assaycontrols for the gene copy in healthy individuals (not shown). The 5′nuclease assay (for example, TaqMan™) and real-time quantitative PCR(for example, ABI Prizm 7700 Sequence Detection System™ (Perkin Elmer,Applied Biosystems Division, Foster City, Calif.)), were used to findgenes potentially amplified in certain cancers. The results were used todetermine whether the DNA encoding the PRO polypeptide isover-represented in any of the primary lung or colon cancers or cancercell lines or breast cancer cell lines that were screened. The primarylung cancers were obtained from individuals with tumors of the type andstage as indicated in Table 8. An explanation of the abbreviations usedfor the designation of the primary tumors listed in Table 8 and theprimary tumors and cell lines referred to throughout this example aregiven below.

The results of the TaqMan™ are reported in delta (Δ) Ct units. One unitcorresponds to 1 PCR cycle or approximately a 2-fold amplificationrelative to normal, two units corresponds to 4-fold, 3 units to 8-foldamplification and so on. Quantitation was obtained using primers and aTaqMan™ fluorescent probe derived from the PRO polypeptide-encodinggene. Regions of the PRO polypeptide-encoding gene which are most likelyto contain unique nucleic acid sequences and which are least likely tohave spliced out introns are preferred for the primer and probederivation, e.g., 3′-untranslated regions. The sequences for the primersand probes (forward, reverse and probe) used for the PRO polypeptidegene amplification analysis were as follows:

PRO187 (DNA27864-1155) 27864.tm.p: 5′-GCAGATTTTGAGGACAGCCACCTCCA-3′ (SEQID NO:381) 27864.tm.f: 5′-GGCCTTGCAGACAACCGT-3′ (SEQ ID NO:382)27864.tm.r: 5′-CAGACTGAGGGAGATCCGAGA-3′ (SEQ ID NO:383) 27864.tm.p2:5′-CAGCTGCCCTTCCCCAACCA-3′ (SEQ ID NO:384) 27864.tm.f2:5′-CATCAAGCGCCTCTACCA-3′ (SEQ ID NO:385) 27864.tm.r2:5′CACAAACTCGAACTGCTTCTG-3′ (SEQ ID NO:386) PRO214 (DNA32286-1191):32286.3utr-5: 5′-GGGCCATCACAGCTCCCT-3′ (SEQ ID NO:387) 32286.3utr-3b:5′-GGGATGTGGTGAACACAGAACA-3′ (SEQ ID NO:388) 32286.3utr-probe:5′-TGCCAGCTGCATGCTGCCAGTT-3′ (SEQ ID NO:389) PRO211 (DNA32292-1131):32292.3utr-5: 5′-CAGAAGGATGTCCCGTGGAA-3′ (SEQ ID NO:390) 32292.3utr-3:5′-GCCGCTGTCCACTGCAG-3′ (SEQ ID NO:391) 32292.3utr-probe.rc:5′GACGGCATCCTCAGGGCCACA-3′ (SEQ ID NO:392) PRO230 (DNA33223-1136):33223.tm.p3: 5′-ATGTCCTCCATGCCCACGCG-3′ (SEQ ID NO:393) 33223.tm.f3:5′-GAGTGCGACATCGAGAGCTT-3′ (SEQ ID NO:394) 33223.tm.r3:5′-CCGCAGCCTCAGTGATGA-3′ (SEQ ID NO:395) 33223.3utr-5:5′-GAAGAGCACAGCTGCAGATCC-3′ (SEQ ID NO:396) 33223.3utr-3:5′-GAGGTGTCCTGGCTTTGGTAGT-3′ (SEQ ID NO:397) 33223.3utr-probe:5′-CCTCTGGCGCCCCCACTCAA-3′ (SEQ ID NO:398) PRO317 (DNA33461-1199):33461.tm.f: 5′-CCAGGAGAGCTGGCGATG-3′ (SEQ ID NO:399) 33461.tm.r:5′-GCAAATTCAGGGCTCACTAGAGA-3′ (SEQ ID NO:400) 33461.tm.p:5′-CACAGAGCATTTGTCCATCAGCAGTTCAG-3′ (SEQ ID NO:401) PRO246(DNA35639-1172): 35639.3utr-5: 5′-GGCAGAGACTTCCAGTCACTGA-3′ (SEQ IDNO:402) 35639.3utr-3: 5′-GCCAAGGGTGGTGTTAGATAGG-3′ (SEQ ID NO:403)35639.3utr-probe: 5′-CAGGCCCCCTTGATCTGTACCCCA-3′ (SEQ ID NO:404) PRO533(DNA49435-1219): 49435.tm.f: 5′-GGGACGTGCCTCTACAAGAACAG-3′ (SEQ IDNO:405) 49435.tm.r: 5′-CAGGCTTACAATGTTATGATCAGACA-3′ (SEQ ID NO:406)49435.tm.p: 5′-TATTCAGAGTTTTCCATTGGCAGTGCCAGTT-3′ (SEQ ID NO:407) PRO343(DNA43318-1217): 43318.tm.f1 5′-TCTACATCAGCCTCTCTGCGC-3′ (SEQ ID NO:408)43318.tm.p1 5′-CGATCTTCTCCACCCAGGAGCGG-3′ (SEQ ID NO:409) 43318.tm.r15′-GGAGCTGCACCCCTTGC-3′ (SEQ ID NO:237) PRO232 (DNA34435-1140):34435.3utr-5: 5′-GCCAGGCCTCACATTCGT-3′ (SEQ ID NO:410)DNA34435.3utr-probe: 5′-CTCCCTGAATGGCAGCCTGAGCA-3′ (SEQ ID NO:411)DNA34435.3utr-3: 5′-AGGTGTTTATTAAGGGCCTACGCT-3′ (SEQ ID NO:412) PRO269(DNA38260-1180): 38260.tm.f: 5′-CAGAGCAGAGGGTGCCTTG-3′ (SEQ ID NO:4133826O.tm.p: 5′-TGGCGGAGTCCCCTCTTGGCT-3′ (SEQ ID NO:414) 38260.tm.r:5′-CCCTGTTTCCCTATGCATCACT-3′ (SEQ ID NO:415) PRO304 (DNA39520-1217):39520.tm.f: 5′-TCAACCCCTGACCCTTTCCTA-3′ (SEQ ID NO:416) 39520.tm.p:5′-GGCAGGGGACAAGCCATCTCTCCT-3′ (SEQ ID NO:417) 39520.tm.r:5′-GGGACTGAACTGCCAGCTTC-3′ (SEQ ID NO:418) PRO339 (DNA43466-1225):43466.tm.f1: 5′-GGGCCCTAACCTCATTACCTTT-3′ (SEQ ID NO:419) 43466.tm.p1:5′-TGTCTGCCTCAGCCCCAGGAAGG-3′ (SEQ ID NO:420) 43466.tm.r1:5′-TCTGTCCACCATCTTGCCTTG-3′ (SEQ ID NO:421)

The 5′ nuclease assay reaction is a fluorescent PCR-based techniquewhich makes use of the 5′ exonuclease activity of Taq DNA polymeraseenzyme to monitor amplification in real time. Two oligonucleotideprimers (forward [.f] and reverse [.r]) are used to generate an amplicontypical of a PCR reaction. A third oligonucleotide, or probe (.p), isdesigned to detect nucleotide sequence located between the two PCRprimers. The probe is non-extendible by Taq DNA polymerase enzyme, andis labeled with a reporter fluorescent dye and a quencher fluorescentdye. Any laser-induced emission from the reporter dye is quenched by thequenching dye when the two dyes are located close together as they areon the probe. During the amplification reaction, the Taq DNA polymeraseenzyme cleaves the probe in a template-dependent manner. The resultantprobe fragments disassociate in solution, and signal from the releasedreporter dye is free from the quenching effect of the secondfluorophore. One molecule of reporter dye is liberated for each newmolecule synthesized, and detection of the unquenched reporter dyeprovides the basis for quantitative interpretation of the data.

The 5′ nuclease procedure is run on a real-time quantitative PCR devicesuch as the ABI Prism 7700TM Sequence Detection. The system consists ofa thermocycler, laser, charge-coupled device (CCD) camera and computer.The system amplifies samples in a 96-well format on a thermocycler.During amplification, laser-induced fluorescent signal is collected inreal-time through fiber optics cables for all 96 wells, and detected atthe CCD. The system includes software for running the instrument and foranalyzing the data.

5′ Nuclease assay data are initially expressed as Ct, or the thresholdcycle. This is defined as the cycle at which the reporter signalaccumulates above the background level of fluorescence. The ΔCt valuesare used as quantitative measurement of the relative number of startingcopies of a particular target sequence in a nucleic acid sample whencomparing cancer DNA results to normal human DNA results.

Table 8 describes the stage, T stage and N stage of various primarytumors which were used to screen the PRO polypeptide compounds of theinvention.

TABLE 8 Primary Lung and Colon Tumor Profiles Primary Tumor Stage StageOther Stage Dukes Stage T Stage N Stage Human lung tumor AdenoCa(SRCC724) [LT1] IIA T1 N1 Human lung tumor SqCCa (SRCC725) [LT1a] IIB T3N0 Human lung tumor AdenoCa (SRCC726) [LT2] IB T2 N0 Human lung tumorAdenoCa (SRCC727) [LT3] IIIA T1 N2 Human lung tumor AdenoCa (SRCC728)[LT4] IB T2 N0 Human lung tumor SqCCa (SRCC729) [LT6] IB T2 N0 Humanlung tumor Aden/SqCCa (SRCC73O) [LT7] IA T1 N0 Human lung tumor AdenoCa(SRCC731) [LT9] IB T2 N0 Human lung tumor SqCCa (SRCC732) [LT10] IIB T2N1 Human lung tumor SqCCa (SRCC733) [LT11] IIA T1 N1 Human lung tumorAdenoCa (SRCC734) [LT12] IV T2 N0 Human lung tumor AdenoSqCCa(SRCC735)[LT13] IB T2 N0 Human lung tumor SqCCa (SRCC736) [LT15] IB T2N0 Human lung tumor SqCCa (SRCC737) [LT16] IB T2 N0 Human lung tumorSqCCa (SRCC738) [LT17] IIB T2 N1 Human lung tumor SqCCa (SRCC739) [LT18]IB T2 N0 Human lung tumor SqCCa (SRCC740) [LT19] IB T2 N0 Human lungtumor LCCa (SRCC741) [LT21] IIB T3 N1 Human lung AdenoCa (SRCC811)[LT22] 1A T1 N0 Human colon AdenoCa (SRCC742) [CT2] M1 D pT4 N0 Humancolon AdenoCa (SRCC743) [CT3] B pT3 N0 Human colon AdenoCa (SRCC744)[CT8] B T3 N0 Human colon AdenoCa (SRCC745) [CT10] A pT2 N0 Human colonAdenoCa (SRCC746) [CT12] MO, R1 B T3 N0 Human colon AdenoCa (SRCC747)[CT14] pMO, RO B pT3 pN0 Human colon AdenoCa (SRCC748) [CT15] M1, R2 DT4 N2 Human colon AdenoCa (SRCC749) [CT16] pMO B pT3 pN0 Human colonAdenoCa (SRCC750) [CT17] C1 pT3 pN1 Human colon AdenoCa (SRCC751) [CT1]MO, R1 B pT3 N0 Human colon AdenoCa (SRCC752) [CT4] B pT3 M0 Human colonAdenoCa (SRCC753) [CT5] G2 C1 pT3 pN0 Human colon AdenoCa (SRCC754)[CT6] pMO, RO B pT3 pN0 Human colon AdenoCa (SRCC755) [CT7] G1 A pT2 pN0Human colon AdenoCa (SRCC756) [CT9] G3 D pT4 pN2 Human colon AdenoCa(SRCC757) [CT11] B T3 N0 Human colon AdenoCa (SRCC758) [CT18] MO, RO BpT3 pN0

DNA Preparation:

DNA was prepared from cultured cell lines, primary tumors, normal humanblood. The isolation was performed using purification kit, buffer setand protease and all from Quiagen, according to the manufacturer'sinstructions and the description below.

Cell Culture Lysis:

Cells were washed and trypsinized at a concentration of 7.5×10⁸ per tipand pelleted by centrifuging at 1000 rpm for 5 minutes at 4° C.,followed by washing again with ½ volume of PBS recentrifugation. Thepellets were washed a third time, the suspended cells collected andwashed 2×with PBS. The cells were then suspended into 10 ml PBS. BufferC1 was equilibrated at 4° C. Qiagen protease #19155 was diluted into6.25 ml cold ddH₂O to a final concentration of 20 mg/ml and equilibratedat 4° C. 10 ml of G2 Buffer was prepared by diluting Qiagen RNAse Astock (100 mg/ml) to a final concentration of 200 μg/ml.

Buffer C1 (10 ml, 4° C.) and ddH2O (40 ml, 4° C.) were then added to the10 ml of cell suspension, mixed by inverting and incubated on ice for 10minutes. The cell nuclei were pelleted by centrifuging in a Beckmanswinging bucket rotor at 2500 rpm at 4° C. for 15 minutes. Thesupernatant was discarded and the nuclei were suspended with a vortexinto 2 ml Buffer C1 (at 4° C.) and 6 ml ddH₂O, followed by a second 4°C. centrifugation at 2500 rpm for 15 minutes. The nuclei were thenresuspended into the residual buffer using 200 μl per tip. G2 buffer (10ml) was added to the suspended nuclei while gentle vortexing wasapplied. Upon completion of buffer addition, vigorous vortexing wasapplied for 30 seconds. Quiagen protease (200 μl, prepared as indicatedabove) was added and incubated at 50° C. for 60 minutes. The incubationand centrifugation was repeated until the lysates were clear (e.g.,incubating additional 30-60 minutes, pelleting at 3000×g for 10 min., 4°C.).

Solid Human Tumor Sample Preparation and Lysis

Tumor samples were weighed and placed into 50 ml conical tubes and heldon ice. Processing was limited to no more than 250 mg tissue perpreparation (1 tip/preparation). The protease solution was freshlyprepared by diluting into 6.25 ml cold ddH₂O to a final concentration of20 mg/ml and stored at 4° C. G2 buffer (20 ml) was prepared by dilutingDNAse A to a final concentration of 200 mg/ml (from 100 mg/ml stock).The tumor tissue was homogenated in 19 ml G2 buffer for 60 seconds usingthe large tip of the polytron in a laminar-flow TC hood in order toavoid inhalation of aerosols, and held at room temperature. Betweensamples, the polytron was cleaned by spinning at 2×30 seconds each in 2L ddH₂O, followed by G2 buffer (50 ml). If tissue was still present onthe generator tip, the apparatus was disassembled and cleaned.

Quiagen protease (prepared as indicated above, 1.0 ml) was added,followed by vortexing and incubation at 50° C. for 3 hours. Theincubation and centrifugation was repeated until the lysates were clear(e.g., incubating additional 30-60 minutes, pelleting at 3000×g for 10min., 4° C.).

Human Blood Preparation and Lysis

Blood was drawn from healthy volunteers using standard infectious agentprotocols and citrated into 10 ml samples per tip. Quiagen protease wasfreshly prepared by dilution into 6.25 ml cold ddH₂O to a finalconcentration of 20 mg/ml and stored at 4° C. G2 buffer was prepared bydiluting RNAse A to a final concentration of 200 μg/ml from 100 mg/mlstock. The blood (10 ml) was placed into a 50 ml conical tube and 10 mlC1 buffer and 30 ml ddH₂O (both previously equilibrated to 4° C.) wereadded, and the components mixed by inverting and held on ice for 10minutes. The nuclei were pelleted with a Beckman swinging bucket rotorat 2500 rpm, 4° C. for 15 minutes and the supernatant discarded. With avortex, the nuclei were suspended into 2 ml C1 buffer (4° C.) and 6 ml1ddH₂O (4° C.). Vortexing was repeated until the pellet then suspendedinto the residual buffer using a 200 μl tip. G2 buffer (100 ml) wereadded to the suspended nuclei while gently vortexing, followed byvigorous vortexing for 30 seconds. Quiagen protease was added (200 μl)and incubated at 50° C. for 60 minutes. The incubation andcentrifugation was repeated until the lysates were clear (e.g.,incubating additional 30-60 minutes, pelleting at 3000×g for 10 min., 4°C.).

Purification of Cleared Lysates

(1) Isolation of Genomic DNA

Genomic DNA was equilibrated (1 sample per maxi tip preparation) with 10ml QBT buffer. QF elution buffer was equilibrated at 50° C. The sampleswere vortexed for 30 seconds, then loaded onto equilibrated tips anddrained by gravity. The tips were washed with 2×15 ml QC buffer. The DNAwas eluted into 30 ml silanized, autoclaved 30 ml Corex tubes with 15 mlQF buffer (50° C.). Isopropanol (10.5 ml) was added to each sample, thetubes covered with parafin and mixed by repeated inversion until the DNAprecipitated. Samples were pelleted by centrifugation in the SS-34 rotorat 15,000 rpm for 10 minutes at 4° C. The pellet location was marked,the supernatant discarded, and 10 ml 70% ethanol (4° C.) was added.Samples were pelleted again by centrifugation on the SS-34 rotor at10,000 rpm for 10 minutes at 4° C. The pellet location was marked andthe supernatant discarded. The tubes were then placed on their side in adrying rack and dried 10 minutes at 37° C., taking care not to overdrythe samples.

After drying, the pellets were dissolved into 1.0 ml TE (pH 8.5) andplaced at 50° C. for 1-2 hours. Samples were held overnight at 4° C. asdissolution continued. The DNA solution was then transferred to 1.5 mltubes with a 26 gauge needle on a tuberculin syringe. The transfer wasrepeated 5× in order to shear the DNA. Samples were then placed at 50°C. for 1-2 hours.

(2) Quantitation of Genomic DNA and Preparation for Gene AmplificationAssay

The DNA levels in each tube were quantified by standard A₂₆₀, A₂₈₀spectrophotometry on a 1:20 dilution (5 μl DNA+95 μl ddH₂O) using the0.1 ml quartz cuvetts in the Beckman DU640 spectrophotometer. A₂₆₀/A₂₈₀ratios were in the range of 1.8-1.9. Each DNA samples was then dilutedfurther to approximately 200 ng/ml in TE (pH 8.5). If the originalmaterial was highly concentrated (about 700 ng/μl), the material wasplaced at 50° C. for several hours until resuspended.

Fluorometric DNA quantitation was then performed on the diluted material(20-600 ng/ml) using the manufacturer's guidelines as modified below.This was accomplished by allowing a Hoeffer DyNA Quant 200 fluorometerto warm-up for about 15 minutes. The Hoechst dye working solution(#H33258, 10 μl, prepared within 12 hours of use) was diluted into 100ml 1×TNE buffer. A 2 ml cuvette was filled with the fluorometersolution, placed into the machine, and the machine was zeroed. pGEM3Zf(+) (2 μl, lot #360851026) was added to 2 ml of fluorometer solutionand calibrated at 200 units. An additional 2 μl of pGEM 3Zf(+) DNA wasthen tested and the reading confirmed at 400+/−10 units. Each sample wasthen read at least in triplicate. When 3 samples were found to be within10% of each other, their average was taken and this value was used asthe quantification value.

The fluorometricly determined concentration was then used to dilute eachsample to 10 ng/μl in ddH₂O. This was done simultaneously on alltemplate samples for a single TaqMan plate assay, and with enoughmaterial to run 500-1000 assays. The samples were tested in triplicatewith Taqman™ primers and probe both B-actin and GAPDH on a single platewith normal human DNA and no-template controls. The diluted samples wereused provided that the CT value of normal human DNA subtracted from testDNA was +/−1 Ct. The diluted, lot-qualified genomic DNA was stored in1.0 ml aliquots at −80° C. Aliquots which were subsequently to be usedin the gene amplification assay were stored at 4° C. Each 1 ml aliquotis enough for 8-9 plates or 64 tests

Gene Amplification Assay

The PRO polypeptide compounds of the invention were screened in thefollowing primary tumors and the resulting ΔCt values greater than orequal to 1.0 are reported in Table 9 below.

TABLE 9 ΔCt values in lung and colon primary tumors and cell line modelsPrimary Tumors or Cell PRO- PRO- PRO- PRO- PRO- PRO- PRO- PRO- PRO- PRO-PRO- PRO- lines 187 533 214 343 211 230 246 317 232 269 304 339 LT7 1.521.04 1.08 LT13 2.74 1.85 2.71 1.88 3.42 1.63 1.90 1.27 1.29 1.04 2.981.83 2.23 2.26 3.22 1.68 2.24 2.44 2.84 2.93 2.15 2.75 2.53 1.82 LT31.57 1.97 1.06 1.86 1.17 LT4 1.17 1.18 LT9 1.42 1.04 1.80 1.03 LT12 2.701.38 2.23 1.51 2.86 1.54 2.54 2.40 1.14 1.15 1.26 2.90 1.49 1.50 1.272.96 2.47 1.74 2.27 2.92 1.25 2.68 2.28 1.34 LT30 1.67 2.13 1.36 LT211.26 1.09 1.50 LT1-a 1.02 1.18 1.29 LT6 1.93 LT10 1.96 1.07 2.57 LT111.09 1.67 1.00 2.05 1.32 3.43 2.20 1.14 1.51 1.39 1.80 1.89 1.14 1.412.33 1.54 1.02 LT15 3.75 1.77 3.62 2.44 4.32 2.11 2.06 1.86 1.36 1.343.92 1.58 1.30 2.16 4.47 1.56 2.76 3.49 3.64 1.63 2.94 3.56 3.32 2.68LT16 2.10 1.66 1.70 1.25 1.15 1.55 1.00 2.04 1.08 1.83 1.33 LT17 1.321.93 1.15 1.85 1.26 2.68 2.29 1.35 1.42 1.68 1.63 1.87 2.30 1.39 1.692.03 1.30 1.10 1.33 1.30 LT18 1.17 1.04 LT19 4.05 1.67 2.09 3.82 2.424.05 1.91 2.51 1.21 1.60 1.15 3.99 1.98 2.55 4.92 1.68 2.03 4.93 1.163.78 4.76 HF-000840 1.58 Calu-1 1.08 SW900 1.86 CT2 3.56 2.49 1.95 1.422.75 3.49 2.36 CT3 2.06 1.15 1.34 CT8 1.01 1.48 1.29 1.58 CT10 1.81 1.841.88 1.00 1.88 1.49 1.55 CT12 1.81 1.74 1.13 CT14 1.82 2.48 2.33 1.361.72 1.24 CT15 1.63 2.06 1.33 1.41 1.04 CT16 1.95 1.78 1.40 CT17 2.042.40 1.74 CT1 1.24 1.22 1.27 1.25 2.41 1.34 1.46 1.14 CT4 1.36 1.77 1.331.32 1.10 1.17 2.05 1.42 1.02 CT5 2.96 1.56 2.68 1.76 2.27 1.33 1.592.99 2.76 1.64 2.39 CT6 1.10 1.33 1.01 1.14 CT7 1.40 1.66 1.39 1.00 CT91.39 1.16 1.09 1.24 1.13 CT11 2.22 2.05 1.55 2.01 1.75 1.48 1.92 2.261.85 1.83 1.12 HF000539 1.57 SW620 1.14 HF000611 4.64 HF000733 1.93 2.33HF000716 1.68 2.82 CT18 1.29

Summary

Because amplification of the various DNA's as described above occurs invarious tumors, it is likely associated with tumor formation and/orgrowth. As a result, antagonists (e.g., antibodies) directed againstthese polypeptides would be expected to be useful in cancer therapy.

Example 94 Detection of PRO Polypeptides that Affect Glucose or FFAUptake by Primary Rat Adipocytes (Assay 94)

This assay is designed to determine whether PRO polypeptides show theability to affect glucose or FFA uptake by adipocyte cells. PROpolypeptides testing positive in this assay would be expected to beuseful for the therapeutic treatment of disorders where either thestimulation or inhibition of glucose uptake by adipocytes would bebeneficial including, for example, obesity, diabetes or hyper- orhypo-insulinemia.

In a 96 well format, PRO polypeptides to be assayed are added to primaryrat adipocytes, and allowed to incubate overnight. Samples are taken at4 and 16 hours and assayed for glycerol, glucose and FFA uptake. Afterthe 16 hour incubation, insulin is added to the media and allowed toincubate for 4 hours. At this time, a sample is taken and glycerol,glucose and FFA uptake is measured. Media containing insulin without thePRO polypeptide is used as a positive reference control. As the PROpolypeptide being tested may either stimulate or inhibit glucose and FFAuptake, results are scored as positive in the assay if greater than 1.5times or less than 0.5 times the insulin control.

The following PRO polypeptides tested positive as stimulators of glucoseand/or FFA uptake in this assay: PRO221, PRO235, PRO245, PRO295, PRO301and PRO332.

The following PRO polypeptides tested positive as inhibitors of glucoseand/or FFA uptake in this assay: PRO214, PRO219, PRO228, PRO222, PRO231and PRO265.

Example 95 Chondrocyte Re-Differentiation Assay (Assay 110)

This assay shows that certain polypeptides of the invention act toinduce redifferentiation of chondrocytes, therefore, are expected to beuseful for the treatment of various bone and/or cartilage disorders suchas, for example, sports injuries and arthritis. The assay is performedas follows. Porcine chondrocytes are isolated by overnight collagenasedigestion of articulary cartilage of metacarpophalangeal joints of 4-6month old female pigs. The isolated cells are then seeded at 25,000cells/cm² in Ham F-12 containing 10% FBS and 4 μg/ml gentamycin. Theculture media is changed every third day and the cells are then seededin 96 well plates at 5,000 cells/well in 100 μl of the same mediawithout serum and 100 μl of the test PRO polypeptide, 5 nM staurosporin(positive control) or medium alone (negative control) is added to give afinal volume of 200 μl/well. After 5 days of incubation at 37° C., apicture of each well is taken and the differentiation state of thechondrocytes is determined. A positive result in the assay occurs whenthe redifferentiation of the chondrocytes is determined to be moresimilar to the positive control than the negative control.

The following polypeptide tested positive in this assay: PRO214, PRO219,PRO229, PRO222, PRO224, PRO230, PRO257, PRO272 and PRO301.

Example 96 Fetal Hemoglobin Induction in an Erythroblastic Cell Line(Assay 107)

This assay is useful for screening PRO polypeptides for the ability toinduce the switch from adult hemoglobin to fetal hemoglobin in anerythroblastic cell line. Molecules testing positive in this assay areexpected to be useful for therapeutically treating various mammalianhemoglobin-associated disorders such as the various thalassemias. Theassay is performed as follows. Erythroblastic cells are plated instandard growth medium at 1000 cells/well in a 96 well format. PROpolypeptides are added to the growth medium at a concentration of 0.2%or 2% and the cells are incubated for 5 days at 37° C. As a positivecontrol, cells are treated with 100 μM hemin and as a negative control,the cells are untreated. After 5 days, cell lysates are prepared andanalyzed for the expression of gamma globin (a fetal marker). A positivein the assay is a gamma globin level at least 2-fold above the negativecontrol.

The following polypeptides tested positive in this assay: PRO221 andPRO245.

Example 97 Mouse Kidney Mesangial Cell Proliferation Assay (Assay 92)

This assay shows that certain polypeptides of the invention act toinduce proliferation of mammalian kidney mesangial cells and, therefore,are useful for treating kidney disorders associated with decreasedmesangial cell function such as Berger disease or other nephropathiesassociated with Schonlein-Henoch purpura, celiac disease, dermatitisherpetiformis or Crohn disease. The assay is performed as follows. Onday one, mouse kidney mesangial cells are plated on a 96 well plate ingrowth media (3:1 mixture of Dulbecco's modified Eagle's medium andHam's F12 medium, 95% fetal bovine serum, 5% supplemented with 14 mMHEPES) and grown overnight. On day 2, PRO polypeptides are diluted at 2concentrations(1% and 0.1%) in serum-free medium and added to the cells.Control samples are serum-free medium alone. On day 4, 20 μl of the CellTiter 96 Aqueous one solution reagent (Progema) was added to each welland the colormetric reaction was allowed to proceed for 2 hours. Theabsorbance (OD) is then measured at 490 nm. A positive in the assay isanything that gives an absorbance reading which is at least 15% abovethe control reading.

The following polypeptide tested positive in this assay: PRO227.

Example 98 Proliferation of Rat Utricular Supporting Cells (Assay 54)

This assay shows that certain polypeptides of the invention act aspotent mitogens for inner ear supporting cells which are auditory haircell progenitors and, therefore, are useful for inducing theregeneration of auditory hair cells and treating hearing loss inmammals. The assay is performed as follows. Rat UEC-4 utricularepithelial cells are aliquoted into 96 well plates with a density of3000 cells/well in 200 μl of serum-containing medium at 33° C. The cellsare cultured overnight and are then switched to serum-free medium at 37°C. Various dilutions of PRO polypeptides (or nothing for a control) arethen added to the cultures and the cells are incubated for 24 hours.After the 24 hour incubation, ³H-thymidine (1 μCi/well) is added and thecells are then cultured for an additional 24 hours. The cultures arethen washed to remove unincorporated radiolabel, the cells harvested andCpm per well determined. Cpm of at least 30% or greater in the PROpolypeptide treated cultures as compared to the control cultures isconsidered a positive in the assay.

The following polypeptides tested positive in this assay: PRO310 andPRO346.

Example 99 Chondrocyte Proliferation Assay (Assay 111)

This assay is designed to determine whether PRO polypeptides of thepresent invention show the ability to induce the proliferation and/orredifferentiation of chondrocytes in culture. PRO polypeptides testingpositive in this assay would be expected to be useful for thetherapeutic treatment of various bone and/or cartilage disorders suchas, for example, sports injuries and arthritis.

Porcine chondrocytes are isolated by overnight collagenase digestion ofarticular cartilage of the metacarpophalangeal joint of 4-6 month oldfemale pigs. The isolated cells are then seeded at 25,000 cells/cm² inHam F-12 containing 10% FBS and 4 μg/ml gentamycin. The culture media ischanged every third day and the cells are reseeded to 25,000 cells/cm²every five days. On day 12, the cells are seeded in 96 well plates at5,000 cells/well in 100 μl of the same media without serum and 100 μl ofeither serum-free medium (negative control), staurosporin (finalconcentration of 5 nM; positive control) or the test PRO polypeptide areadded to give a final volume of 200 μl/well. After 5 days at 37° C., 20μl of Alamar blue is added to each well plates are incubated for anadditional 3 hours at 37° C. The fluorescence is then measured in eachwell (Ex: 530 nm; Em: 590 nm). The fluorescence of a plate containing200 μl of the serum-free medium is measured to obtain the background. Apositive result in the assay is obtained when the fluorescence of thePRO polypeptide treated sample is more like that of the positive controlthan the negative control.

The following PRO polypeptides tested positive in this assay: PRO219,PRO222, PRO317, PRO257, PRO265, PRO287, PRO272 and PRO533.

Example 100 Inhibition of Heart Neonatal Hypertrophy Induced by LIF+ET-1(Assay 74)

This assay is designed to determine whether PRO polypeptides of thepresent invention show the ability to inhibit neonatal heart hypertrophyinduced by LIF and endothelin-1 (ET-1). A test compound that provides apositive response in the present assay would be useful for thetherapeutic treatment of cardiac insufficiency diseases or disorderscharacterized or associated with an undesired hypertrophy of the cardiacmuscle.

Cardiac myocytes from 1-day old Harlan Sprague Dawley rats (180 μl at7.5×10⁴/ml, serum<0.1, freshly isolated) are introduced on day 1 to96-well plates previously coated with DMEM/F12+4% FCS. Test PROpolypeptide samples or growth medium alone (negative control) are thenadded directly to the wells on day 2 in 20 μl volume LIF+ET-1 are thenadded to the wells on day 3. The cells are stained after an additional 2days in culture and are then scored visually the next day. A positive inthe assay occurs when the PRO polypeptide treated myocytes are visuallysmaller on the average or less numerous than the untreated myocytes.

The following PRO polypeptides tested positive in this assay: PRO238.

Example 101 Tissue Expression Distribution

Oligonucleotide probes were constructed from some of the PROpolypeptide-encoding nucleotide sequences shown in the accompanyingfigures for use in quantitative PCR amplification reactions. Theoligonucleotide probes were chosen so as to give an approximately200-600 base pair amplified fragment from the 3′ end of its associatedtemplate in a standard PCR reaction. The oligonucleotide probes wereemployed in standard quantitative PCR amplification reactions with cDNAlibraries isolated from different human adult and/or fetal tissuesources and analyzed by agarose gel electrophoresis so as to obtain aquantitative determination of the level of expression of the PROpolypeptide-encoding nucleic acid in the various tissues tested.Knowledge of the expression pattern or the differential expression ofthe PRO polypeptide-encoding nucleic acid in various different humantissue types provides a diagnostic marker useful for tissue typing, withor without other tissue-specific markers, for determining the primarytissue source of a metastatic tumor, and the like. These assays providedthe following results.

DNA Molecule Tissues With Significant Expression Tissues LackingSignificant Expression DNA34436-1238 lung, placenta, brain testisDNA35557-1137 lung, kidney, brain placenta DNA35599-1168 kidney, brainliver, placenta DNA35668-1171 liver, lung, kidney placenta, brainDNA36992-1168 liver, lung, kidney, brain placenta DNA39423-1182 kidney,brain liver DNA40603-1232 liver brain, kidney, lung DNA40604-1187 liverbrain, kidney, lung DNA41379-1236 lung, brain liver DNA33206-1165 heart,spleen, dendrocytes substantia nigra, hippocampus, cartilage, prostate,HUVEC DNA34431-1177 spleen, HUVEC, cartilage, heart, uterus brain, colontumor, prostate, THP-1 macrophages DNA41225-1217 HUVEC, uterus, colontumor, cartilage, spleen, brain, heart, IM-9 lymphoblasts prostate

Example 102 In Situ Hybridization

In situ hybridization is a powerful and versatile technique for thedetection and localization of nucleic acid sequences within cell ortissue preparations. It may be useful, for example, to identify sites ofgene expression, analyze the tissue distribution of transcription,identify and localize viral infection, follow changes in specific mRNAsynthesis and aid in chromosome mapping.

In situ hybridization was performed following an optimized version ofthe protocol by Lu and Gillett, Cell Vision 1:169-176 (1994), usingPCR-generated ³³P-labeled riboprobes. Briefly, formalin-fixed,paraffin-embedded human tissues were sectioned, deparaffinized,deproteinated in proteinase K (20 g/ml) for 15 minutes at 37° C., andfurther processed for in situ hybridization as described by Lu andGillett, supra. A [³³-P] UTP-labeled antisense riboprobe was generatedfrom a PCR product and hybridized at 55° C. overnight. The slides weredipped in Kodak NTB2 nuclear track emulsion and exposed for 4 weeks.

³³P-Riboprobe Synthesis

6.0 μl (125 mCi) of ³³P-UTP (Amersham BF 1002, SA<2000 Ci/mmol) werespeed vac dried. To each tube containing dried ³³P-UTP, the followingingredients were added:

2.0 μl 5×transcription buffer

1.0 μl DTT (100 mM)

2.0 μl NTP mix (2.5 nM: 10μ; each of 10 mM GTP, CTP & ATP+10 μl H₂O)

1.0 μl UTP (50 μM)

1.0 μl Rnasin

1.0 μl DNA template (1 μg)

1.0 μl H₂O

1.0 μl RNA polymerase (for PCR products T3=AS, T7=S, usually)

The tubes were incubated at 37° C. for one hour. 1.0 μl RQ1 DNase wereadded, followed by incubation at 37° C. for 15 minutes. 90 μl (10 mMTris pH 7.6/1 mM EDTA pH 8.0) were added, and the mixture was pipettedonto DE81 paper. The remaining solution was loaded in a Microcon-50ultrafiltration unit, and spun using program 10 (6 minutes). Thefiltration unit was inverted over a second tube and spun using program 2(3 minutes). After the final recovery spin, 100 μl TE were added. 1 μlof the final product was pipetted on DE81 paper and counted in 6 ml ofBiofluor II.

The probe was run on a TBE/urea gel. 1-3 μl of the probe or 5 IL of RNAMrk III were added to 3 μl of loading buffer. After heating on a 95° C.heat block for three minutes, the gel was immediately placed on ice. Thewells of gel were flushed, the sample loaded, and run at 180-250 voltsfor 45 minutes. The gel was wrapped in saran wrap and exposed to XARfilm with an intensifying screen in −70° C. freezer one hour toovernight.

³³P-Hybridization

A. Pretreatment of Frozen Sections

The slides were removed from the freezer, placed on aluminum trays andthawed at room temperature for 5 minutes. The trays were placed in 55°C. incubator for five minutes to reduce condensation. The slides werefixed for 10 minutes in 4% paraformaldehyde on ice in the fame hood, andwashed in 0.5×SSC for 5 minutes, at room temperature (25 ml 20×SSC+975ml SQ H₂O). After deproteination in 0.5 μg/ml K for 10 minutes at 37° C.(12.5 μl of 10 mg/ml stock in 250 ml prewarmed RNase-free RNAse buffer),the sections were washed in 0.5×SSC for 10 minutes at room temperature.The sections were dehydrated in 70%, 95%, 100% ethanol, 2 minutes each.

B. Pretreatment of Paraffin-Embedded Sections

The slides were deparaffinized, placed in SQ H₂O, and rinsed twice in2×SSC at room temperature, for 5 minutes each time. The sections weredeproteinated in 20 μg/ml proteinase K (500 μl of 10 mg/ml in 250 mlRNase-free RNase buffer; 37° C., 15 minutes)—human embryo, or8×proteinase K (100 μl in 250 ml Rnase buffer, 37° C., 30minutes)—formalin tissues. Subsequent rinsing in 0.5×SSC and dehydrationwere performed as described above.

C. Prehybridization

The slides were laid out in a plastic box lined with Box buffer (4×SSC,50% formamide)—saturated filter paper. The tissue was covered with 50 μlof hybridization buffer (3.75 g Dextran Sulfate+6 ml SQ H₂O), vortexedand heated in the microwave for 2 minutes with the cap loosened. Aftercooling on ice, 18.75 ml formamide, 3.75 ml 20×SSC and 9 ml SQ H₂O wereadded, the tissue was vortexed well, and incubated at 42° C. for 1-4hours.

D. Hybridization

1.0×10⁶ cpm probe and 1.0 μl tRNA (50 mg/mi stock) per slide were heatedat 95° C. for 3 minutes. The slides were cooled on ice, and 48 μlhybridization buffer were added per slide. After vortexing, 50 μl ³³Pmix were added to 50 μl prehybridization on slide. The slides wereincubated overnight at 55° C.

E. Washes

Washing was done 2×10 minutes with 2×SSC, EDTA at room temperature (400ml 20×SSC+16 ml 0.25M EDTA, V_(f)=4 L), followed by RNaseA treatment at37° C. for 30 minutes (500 μl of 10 mg/ml in 250 ml Rnase buffer=20μg/ml), The slides were washed 2×10 minutes with 2×SSC, EDTA at roomtemperature. The stringency wash conditions were as follows: 2 hours at55° C., 0.1×SSC, EDTA (20 ml 20×SSC+16 ml EDTA, V_(f)=4 L).

F. Oligonucleotides

In situ analysis was performed on a variety of DNA sequences disclosedherein. The oligonucleotides employed for these analyses are as follows.

 (1) DNA33094-1131 (PRO217) p15′-GGATTCTAATACGACTCACTATAGGGCTCAGAAAAGCGCAACAGAGAA-3′ (SEQ ID NO:348)p2 5′-CTATGAAATTAACCCTCACTAAAGGGATGTCTTCCATGCCAACCTTC-3′ (SEQ ID NO:349) (2) DNA33223-1136 (PRO230) p15′-GGATTCTAATACGACTCACTATAGGGCGGCGATGTCCACTGGGGCTAC-3′ (SEQ ID NO:350)p2 5′-CTATGAAATTAACCCTCACTAAAGGGACGAGGAAGATGGGCGGATGGT-3′ (SEQ IDNO:351)  (3) DNA34435-1140 (PRO232) p15′-GGATTCTAATACGACTCACTATAGGGCACCCACGCGTCCGGCTGCTT-3′ (SEQ ID NO:352) p25′-CTATGAAATTAACCCTCACTAAAGGGACGGGGGACACCACGGACCAGA-3′ (SEQ ID NO:353) (4) DNA35639-1172 (PRO246) p15′-GGATTCTAATACGACTCACTATAGGGCTTGCTGCGGTTTTTGTTCCTG-3′ (SEQ ID NO:354)p2 5′-CTATGAAATTAACCCTCACTAAAGGGAGCTGCCGATCCCACTGGTATT-3′ (SEQ IDNO:355)  (5) DNA49435-1219 (PRO533) p15′-GGATTCTAATACGACTCACTATAGGGCGGATCCTGGCCGGCCTCTG-3′ (SEQ ID NO:356) p25′-CTATGAAATTAACCCTCACTAAAGGGAGCCCGGGCATGGTCTCAGTTA-3′ (SEQ ID NO:357) (6) DNA35638-1141 (PRO245) p15′-GGATTCTAATACGACTCACTATAGGGCGGGAAGATGGCGAGGAGGAG-3′ (SEQ ID NO:358) p25′-CTATGAAATTAACCCTCACTAAAGGGACCAAGGCCACAAACGGAAATC-3′ (SEQ ID NO:359) (7) DNA33089-1132 (PRO221) p15′-GGATTCTAATACGACTCACTATAGGGCTGTGCTTTCATTCTGCCAGTA-3′ (SEQ ID NO:360)p2 5′-CTATGAAATTAACCCTCACTAAAGGGAGGGTACAATTAAGGGGTGGAT-3′ (SEQ IDNO:361)  (8) DNA35918-1174 (PRO258) p15′-GGATTCTAATACGACTCACTATAGGGCCCGCCTCGCTCCTGCTCCTG-3′ (SEQ ID NO:362) p25′-CTATGAAATTAACCCTCACTAAAGGGAGGATTGCCGCGACCCTCACAG-3′ (SEQ ID NO:363) (9) DNA32286-1191 (PRO214) p15′-GGATTCTAATACGACTCACTATAGGGCCCCTCCTGCCTTCCCTGTCC-3′ (SEQ ID NO:364) p25′-CTATGAAATTAACCCTCACTAAAGGGAGTGGTGGCCGCGATTATCTGC-3′ (SEQ ID NO:365)(10) DNA33221-1133 (PRO224) p15′-GGATTCTAATACGACTCACTATAGGGCGCAGCGATGGCAGCGATGAGG-3′ (SEQ ID NO:366)p2 5′-CTATGAAATTAACCCTCACTAAAGGGACAGACGGGGCAGAGGGAGTG-3′ (SEQ ID NO:367)(11) DNA35557-1137 (PRO234) p15′-GGATTCTAATACGACTCACTATAGGGCCAGGAGGCGTGAGGAGAAAC-3′ (SEQ ID NO:368) p25′-CTATGAAATTAACCCTCACTAAAGGGAAAGACATGTCATCGGGAGTGG-3′ (SEQ ID NO:369)(12) DNA33100-1159 (PRO229) p15′-GGATTCTAATACGACTCACTATAGGGCCGGGTGGAGGTGGAACAGAAA-3′ (SEQ ID NO:370)p2 5′-CTATGAAATTAACCCTCACTAAAGGGACACAGACAGAGCCCCATACGC-3′ (SEQ IDNO:371) (13) DNA34431-1177 (PRO263) p15′-GGATTCTAATACGACTCACTATAGGGCCAGGGAAATCCGGATGTCTC-3′ (SEQ ID NO:372) p25′-CTATGAAATTAACCCTCACTAAAGGGAGTAAGGGGATGCCACCGAGTA-3′ (SEQ ID NO:373)(14) DNA38268-1188 (PRO295) p15′-GGATTCTAATACGACTCACTATAGGGCCAGCTACCCGCAGGAGGAGG-3′ (SEQ ID NO:374) p25′-CTATGAAATTAACCCTCACTAAAGGGATCCCAGGTGATGAGGTCCAGA-3′ (SEQ ID NO:375)

G. Results

In situ analysis was performed on a variety of DNA sequences disclosedherein. The results from these analyses are as follows.

(1) DNA33094-1131 (PRO217)

Highly distinctive expression pattern, that does not indicate an obviousbiological function. In the human embryo it was expressed in outersmooth muscle layer of the GI tract, respiratory cartilage, branchingrespiratory epithelium, osteoblasts, tendons, gonad, in the optic nervehead and developing dermis. In the adult expression was observed in theepidermal pegs of the chimp tongue, the basal epithelial/myoepithelialcells of the prostate and urinary bladder. Also expressed in thealveolar lining cells of the adult lung, mesenchymal cells juxtaposed toerectile tissue in the penis and the cerebral cortex (probably glialcells). In the kidney, expression was only seen in disease, in cellssurrounding thyroidized renal tubules.

Human fetal tissues examined (E12-E16 weeks) include: Placenta,umbilical cord, liver, kidney, adrenals, thyroid, lungs, heart, greatvessels, oesophagus, stomach, small intestine, spleen, thymus, pancreas,brain, eye, spinal cord, body wall, pelvis and lower limb.

Adult human tissues examined: Kidney (normal and end-stage), adrenal,myocardium, aorta, spleen, lymph node, gall bladder, pancreas, lung,skin, eye (inc. retina), prostate, bladder, liver (normal, cirrhotic,acute failure).

Non-human primate tissues examined:

(a) Chimp, Tissues: Salivary gland, stomach, thyroid, parathyroid, skin,thymus, ovary, lymph node.

(b) Rhesus Monkey Tissues: Cerebral cortex, hippocampus, cerebellum,penis.

(2) DNA33223-1136 (PRO230)

Sections show an intense signal associated with arterial and venousvessels in the fetus. In arteries the signal appeared to be confined tosmooth-muscle/pericytic cells. The signal is also seen in capillaryvessels and in glomeruli. It is not clear whether or not endothelialcells are expressing this mRNA. Expression is also observed inepithelial cells in the fetal lens. Strong expression was also seen incells within placental trophoblastic villi, these cells lie between thetrophoblast and the fibroblast-like cells that express HGF-uncertainhistogenesis. In the adult, there was no evidence of expression and thewall of the aorta and most vessels appear to be negative. However,expression was seen over vascular channels in the normal prostate and inthe epithelium lining the gallbladder. Insurers expression was seen inthe vessels of the soft-tissue sarcoma and a renal cell carcinoma. Insummary, this is a molecule that shows relatively specific vascularexpression in the fetus as well as in some adult organs. Expression wasalso observed in the fetal lens and the adult gallbladder.

In a secondary screen, vascular expression was observed, similar to thatobserved above, seen in fetal blocks. Expression is on vascular smoothmuscle, rather than endothelium. Expression also seen in smooth muscleof the developing oesophagus, so as reported previously, this moleculeis not vascular specific. Expression was examined in 4 lung and 4 breastcarcinomas. Substantial expression was seen in vascular smooth muscle ofat least 3/4 lung cancers and 2/4 breast cancers. In addition, in onebreast carcinoma, expression was observed in peritumoral stromal cellsof uncertain histogenesis (possibly myofibroblasts). No endothelial cellexpression was observed in this study.

(3) DNA34435-1140 (PRO232)

Strong expression in prostatic epithelium and bladder epithelium, lowerlevel of expression in bronchial epithelium. High background/low levelexpression seen in a number of sites, including among others, bone,blood, chondrosarcoma, adult heart and fetal liver. It is felt that thislevel of signal represents background, partly because signal at thislevel was seen over the blood. All other tissues negative.

Human fetal tissues examined (E12-E16 weeks) include: Placenta,umbilical cord, liver, kidney, adrenals, thyroid, lungs, heart, greatvessels, oesophagus, stomach, small intestine, spleen, thymus, pancreas,brain, eye, spinal cord, body wall, pelvis, testis and lower limb.

Adult human tissues examined: Kidney (normal and end-stage), adrenal,spleen, lymph node, pancreas, lung, eye (inc. retina), bladder, liver(normal, cirrhotic, acute failure).

Non-human primate tissues examined:

Chimp Tissues: adrenal

Rhesus Monkey Tissues: Cerebral cortex, hippocampus

In a secondary screen, expression was observed in the epithelium of theprostate, the superficial layers of the urethelium of the urinarybladder, the urethelium lining the renal pelvis and the urethelium ofthe ureter (1 out of 2 experiments). The urethra of a rhesus monkey wasnegative; it is unclear whether this represents a true lack ofexpression by the urethra, or if it is the result of a failure of theprobe to cross react with rhesus tissue. The findings in the prostateand bladder are similar to those previously described using an isotopicdetection technique. Expression of the mRNA for this antigen is NOTprostate epithelial specific. The antigen may serve as a useful markerfor urethelial derived tissues. Expression in the superficial,post-mitotic cells, of the urinary tract epithelium also suggest that itis unlikely to represent a specific stem cell marker, as this would beexpected to be expressed specifically in basal epithelium.

(4) DNA35639-1172 (PRO246)

Strongly expressed in fetal vascular endothelium, including tissues ofthe CNS. Lower level of expression in adult vasculature, including theCNS. Not obviously expressed at higher levels in tumor vascularendothelium. Signal also seen over bone matrix and adult spleen, notobviously cell associated, probably related to non-specific backgroundat these sites.

Human fetal tissues examined (E12-E16 weeks) include: Placenta,umbilical cord, liver, kidney, adrenals, thyroid, lungs, heart, greatvessels, oesophagus, stomach, small intestine, spleen, thymus, pancreas,brain, eye, spinal cord, body wall, pelvis, testis and lower limb.

Adult human tissues examined: Kidney (normal and end-stage), adrenal,spleen, lymph node, pancreas, lung, eye (inc. retina), bladder, liver(normal, cirrhotic, acute failure).

Non-human primate tissues examined:

Chimp Tissues: adrenal

Rhesus Monkey Tissues: Cerebral cortex, hippocampus

(5) DNA49435-1219 (PRO533)

Moderate expression over cortical neurones in the fetal brain.Expression over the inner aspect of the fetal retina, possibleexpression in the developing lens. Expression over fetal skin,cartilage, small intestine, placental villi and umbilical cord. In adulttissues there is an extremely high level of expression over thegallbladder epithelium. Moderate expression over the adult kidney,gastric and colonic epithelia. Low-level expression was observed overmany cell types in many tissues, this may be related to stickiness ofthe probe, these data should therefore be interpreted with a degree ofcaution.

Human fetal tissues examined (E12-E16 weeks) include: Placenta,umbilical cord, liver, kidney, adrenals, thyroid, lungs, heart, greatvessels, oesophagus, stomach, small intestine, spleen, thymus, pancreas,brain, eye, spinal cord, body wall, pelvis, testis and lower limb.

Adult human tissues examined: Kidney (normal and end-stage), adrenal,spleen, lymph node, pancreas, lung, eye (inc. retina), bladder, liver(normal, cirrhotic, acute failure).

Non-human primate tissues examined:

Chimp Tissues: adrenal

Rhesus Monkey Tissues: Cerebral cortex, hippocampus, cerebellum.

(6) DNA35638-1141 (PRO245)

Expression observed in the endothelium lining a subset of fetal andplacental vessels. Endothelial expression was confined to these tissueblocks. Expression also observed over intermediate trophoblast cells ofplacenta. Expression also observed tumor vasculature but not in thevasculature of normal tissues of the same type. All other tissuesnegative.

Fetal tissues examined (E12-E16 weeks) include: Placenta, umbilicalcord, liver, kidney, adrenals, thyroid, lungs, heart, great vessels,oesophagus, stomach, small intestine, spleen, thymus, pancreas, brain,eye, spinal cord, body wall, pelvis and lower limb.

Adult tissues examined: Liver, kidney, adrenal, myocardium, aorta,spleen, lymph node, pancreas, lung, skin, cerebral cortex (rm),hippocampus(rm), cerebellum(rm), penis, eye, bladder, stomach, gastriccarcinoma, colon, colonic carcinoma, thyroid (chimp), parathyroid(chimp) ovary (chimp) and chondrosarcoma. Acetominophen induced liverinjury and hepatic cirrhosis

(7) DNA33089-1132 (PRO221)

Specific expression over fetal cerebral white and grey matter, as wellas over neurones in the spinal cord. Probe appears to cross react withrat. Low level of expression over cerebellar neurones in adult rhesusbrain. All other tissues negative.

Fetal tissues examined (E12-E16 weeks) include: Placenta, umbilicalcord, liver, kidney, adrenals, thyroid, lungs, heart, great vessels,oesophagus, stomach, small intestine, spleen, thymus, pancreas, brain,eye, spinal cord, body wall, pelvis and lower limb.

Adult tissues examined: Liver, kidney, adrenal, myocardium, aorta,spleen, lymph node, pancreas, lung, skin, cerebral cortex (rm),hippocampus(rm), cerebellum(rm), penis, eye, bladder, stomach, gastriccarcinoma, colon, colonic carcinoma and chondrosarcoma. Acetominopheninduced liver injury and hepatic cirrhosis

(8) DNA35918-1174 (PRO258)

Strong expression in the nervous system. In the rhesus monkey brainexpression is observed in cortical, hippocampal and cerebellar neurones.Expression over spinal neurones in the fetal spinal cord, the developingbrain and the inner aspects of the fetal retina. Expression overdeveloping dorsal root and autonomic ganglia as well as enteric nerves.Expression observed over ganglion cells in the adult prostate. In therat, there is strong expression over the developing hind brain andspinal cord. Strong expression over interstitial cells in the placentalvilli. All other tissues were negative.

Fetal tissues examined (E12-E16 weeks) include: Placenta, umbilicalcord, liver, kidney, adrenals, thyroid, lungs, heart, great vessels,oesophagus, stomach, small intestine, spleen, thymus, pancreas, brain,eye, spinal cord, body wall, pelvis and lower limb.

Adult tissues examined: Liver, kidney, renal cell carcinoma, adrenal,aorta, spleen, lymph node, pancreas, lung, myocardium, skin, cerebralcortex (rm), hippocampus(rm), cerebellum(rm), bladder, prostate,stomach, gastric carcinoma, colon, colonic carcinoma, thyroid (chimp),parathyroid (chimp) ovary (chimp) and chondrosarcoma. Acetominopheninduced liver injury and hepatic cirrhosis.

(9) DNA32286-1191 (PRO214)

Fetal tissue: Low level throughout mesenchyme. Moderate expression inplacental stromal cells in membranous tissues and in thyroid. Low levelexpression in cortical neurones. Adult tissue: all negative.

Fetal tissues examined (E12-E16 weeks) include: Placenta, umbilicalcord, liver, kidney, adrenals, thyroid, lungs, heart, great vessels,oesophagus, stomach, small intestine, spleen, thymus, pancreas, brain,eye, spinal cord, body wall, pelvis and lower limb.

Adult tissues examined include: Liver, kidney, adrenal, myocardium,aorta, spleen, lymph node, pancreas, lung and skin.

(10) DNA33221-1133 (PRO224)

Expression limited to vascular endothelium in fetal spleen, adultspleen, fetal liver, adult thyroid and adult lymph node (chimp).Additional site of expression is the developing spinal ganglia. Allother tissues negative.

Human fetal tissues examined (E12-E16 weeks) include: Placenta,umbilical cord, liver, kidney, adrenals, thyroid, lungs, heart, greatvessels, oesophagus, stomach, small intestine, spleen, thymus, pancreas,brain, eye, spinal cord, body wall, pelvis and lower limb.

Adult human tissues examined: Kidney (normal and end-stage), adrenal,myocardium, aorta, spleen, lymph node, pancreas, lung, skin, eye (inc.retina), bladder, liver (normal, cirrhotic, acute failure).

Non-human primate tissues examined:

Chimp Tissues: Salivary gland, stomach, thyroid, parathyroid, skin,thymus, ovary, lymph node.

Rhesus Monkey Tissues: Cerebral cortex, hippocampus, cerebellum, penis.

(11) DNA35557-1137 (PRO234)

Specific expression over developing motor neurones in ventral aspect ofthe fetal spinal cord (will develop into ventral horns of spinal cord).All other tissues negative. Possible role in growth, differentiationand/or development of spinal motor neurons.

Fetal tissues examined (E12-E16 weeks) include: Placenta, umbilicalcord, liver, kidney, adrenals, thyroid, lungs, heart, great vessels,oesophagus, stomach, small intestine, spleen, thymus, pancreas, brain,eye, spinal cord, body wall, pelvis and lower limb.

Adult tissues examined: Liver, kidney, adrenal, myocardium, aorta,spleen, lymph node, pancreas, lung, skin, cerebral cortex (rm),hippocampus(rm), cerebellum(rm), penis, eye, bladder, stomach, gastriccarcinoma, colon, colonic carcinoma and chondrosarcoma. Acetominopheninduced liver injury and hepatic cirrhosis

(12) DNA33100-1159 (PRO229)

Striking expression in mononuclear phagocytes (macrophages) of fetal andadult spleen, liver, lymph node and adult thymus (in tingible bodymacrophages). The highest expression is in the spleen. All other tissuesnegative. Localisation and homology are entirely consistent with a roleas a scavenger receptor for cells of the reticuloendothelial system.Expression also observed in placental mononuclear cells.

Human fetal tissues examined (E12-E16 weeks) include: Placenta,umbilical cord, liver, kidney, adrenals, thyroid, lungs, heart, greatvessels, oesophagus, stomach, small intestine, spleen, thymus, pancreas,brain, eye, spinal cord, body wall, pelvis and lower limb.

Adult human tissues examined: Kidney (normal and end-stage), adrenal,myocardium, aorta, spleen, lymph node, gall bladder, pancreas, lung,skin, eye (inc. retina), prostate, bladder, liver (normal, cirrhotic,acute failure).

Non-human primate tissues examined:

Chimp Tissues: Salivary gland, stomach, thyroid, parathyroid, skin,thymus, ovary, lymph node.

Rhesus Monkey Tissues: Cerebral cortex, hippocampus, cerebellum, penis.

(13) DNA34431-1177 (PRO263)

Widepread expression in human fetal tissues and placenta overmononuclear cells, probably macrophages +/− lymphocytes. The cellulardistribution follows a perivascular pattern in many tissues. Strongexpression also seen in epithelial cells of the fetal adrenal cortex.All adult tissues were negative.

Fetal tissues examined (E12-E16 weeks) include: Placenta, umbilicalcord, liver, kidney, adrenals, thyroid, lungs, heart, great vessels,oesophagus, stomach, small intestine, spleen, thymus, pancreas, brain,eye, spinal cord, body wall, pelvis and lower limb.

Adult tissues examined: Liver, kidney, adrenal, spleen, lymph node,pancreas, lung, skin, cerebral cortex (rm), hippocampus(rm),cerebellum(rm), bladder, stomach, colon and colonic carcinoma.Acetominophen induced liver injury and hepatic cirrhosis.

A secondary screen evidenced expression over stromal mononuclear cellsprobably histiocytes.

(14) DNA38268-1188 (PRO295)

High expression over ganglion cells in human fetal spinal ganglia andover large neurones in the anterior horns of the developing spinal cord.In the adult there is expression in the chimp adrenal medulla (neural),neurones of the rhesus monkey brain (hippocampus [+++] and cerebralcortex) and neurones in ganglia in the normal adult human prostate (theonly section that contains ganglion cells, ie expression in this celltype is presumed NOT to be confined to the prostate). All other tissuesnegative.

Human fetal tissues examined (E12-E16 weeks) include: Placenta,umbilical cord, liver, kidney, adrenals, thyroid, lungs, great vessels,stomach, small intestine, spleen, thymus, pancreas, brain, eye, spinalcord, body wall, pelvis, testis and lower limb.

Adult human tissues examined: Kidney (normal and end-stage), adrenal,spleen, lymph node, pancreas, lung, eye (inc. retina), bladder, liver(normal, cirrhotic, acute failure).

Non-human primate tissues examined:

Chimp Tissues: adrenal

Rhesus Monkey Tissues: Cerebral cortex, hippocampus, cerebellum.

Example 103 Isolation of cDNA Clones Encoding Human PRO1868

A consensus DNA sequence was assembled relative to other EST sequencesusing phrap as described in Example 1 above. This consensus sequence isherein designated DNA49803. Based up an observed homology between theDNA49803 consensus sequence and an EST sequence contained within theIncyte EST clone no. 2994689, Incyte EST clone no. 2994689 was purchasedand its insert obtained and sequenced. The sequence of that insert isshown in FIG. 123 and is herein designated DNA77624-2515.

The entire nucleotide sequence of DNA77624-2515 is shown in FIG. 123(SEQ ID NO:422). Clone DNA77624-2515 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 51-53 and ending at the stop codon at nucleotide positions981-983 (FIG. 123). The predicted polypeptide precursor is 310 aminoacids long (FIG. 124). The full-length PRO1868 protein shown in FIG. 124has an estimated molecular weight of about 35,020 daltons and a pI ofabout 7.90. Analysis of the full-length PRO1868 sequence shown in FIG.124 (SEQ ID NO:423) evidences the presence of the following: a signalpeptide from about amino acid 1 to about amino acid 30, a transmembranedomain from about amino acid 243 to about amino acid 263, potentialN-glycosylation sites from about amino acid 104 to about amino acid 107and from about amino acid 192 to about amino acid 195, a cAMP- andcGMP-dependent protein kinase phosphorylation site from about amino acid107 to about amino acid 110, casein kinase II phosphorylation sites fromabout amino acid 106 to about amino acid 109 and from about amino acid296 to about amino acid 299, a tyrosine kinase phosphorylation site fromabout amino acid 69 to about amino acid 77 and potential N-myristolationsites from about amino acid 26 to about amino acid 31, from about aminoacid 215 to about amino acid 220, from about amino acid 226 to aboutamino acid 231, from about amino acid 243 to about amino acid 248, fromabout amino acid 244 to about amino acid 249 and from about amino acid262 to about amino acid 267. Clone DNA77624-2515 has been deposited withATCC on Dec. 22, 1998 and is assigned ATCC deposit no. 203553.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), usinga WU-BLAST2 sequence alignment analysis of the full-length sequenceshown in FIG. 124 (SEQ ID NO:423), evidenced significant homologybetween the PRO1868 amino acid sequence and the following Dayhoffsequences: HGS_RC75, P_W61379, A33_HUMAN, P_W14146, P_W14158,AMAL_DROME, P_R77437, I38346, NCM2_HUMAN and PTPD_HUMAN.

Example 104 Identification of Receptor/Ligand Interactions

In this assay, various PRO polypeptides are tested for ability to bindto a panel of potential receptor molecules for the purpose ofidentifying receptor/ligand interactions. The identification of a ligandfor a known receptor, a receptor for a known ligand or a novelreceptor/ligand pair is useful for a variety of indications including,for example, targeting bioactive molecules (linked to the ligand orreceptor) to a cell known to express the receptor or ligand, use of thereceptor or ligand as a reagent to detect the presence of the ligand orreceptor in a composition suspected of containing the same, wherein thecomposition may comprise cells suspected of expressing the ligand orreceptor, modulating the growth of or another biological orimmunological activity of a cell known to express or respond to thereceptor or ligand, modulating the immune response of cells or towardcells that express the receptor or ligand, allowing the preparaion ofagonists, antagonists and/or antibodies directed against the receptor orligand which will modulate the growth of or a biological orimmunological activity of a cell expressing the receptor or ligand, andvarious other indications which will be readily apparent to theordinarily skilled artisan.

The assay is performed as follows. A PRO polypeptide of the presentinvention suspected of being a ligand for a receptor is expressed as afusion protein containing the Fc domain of human IgG (an immunoadhesin).Receptor-ligand binding is detected by allowing interaction of theimmunoadhesin polypeptide with cells (e.g. Cos cells) expressingcandidate PRO polypeptide receptors and visualization of boundimmunoadhesin with fluorescent reagents directed toward the Fc fusiondomain and examination by microscope. Cells expressing candidatereceptors are produced by transient transfection, in parallel, ofdefined subsets of a library of cDNA expression vectors encoding PROpolypeptides that may function as receptor molecules. Cells are thenincubated for 1 hour in the presence of the PRO polypeptideimmunoadhesin being tested for possible receptor binding. The cells arethen washed and fixed with paraformaldehyde. The cells are thenincubated with fluorescent conjugated antibody directed against the Fcportion of the PRO polypeptide immunoadhesin (e.g. FITC conjugated goatanti-human-Fc antibody). The cells are then washed again and examined bymicroscope. A positive interaction is judged by the presence offluorescent labeling of cells transfected with cDNA encoding aparticular PRO polypeptide receptor or pool of receptors and an absenceof similar fluorescent labeling of similarly prepared cells that havebeen transfected with other cDNA or pools of cDNA. If a defined pool ofcDNA expression vectors is judged to be positive for interaction with aPRO polypeptide immunoadhesin, the individual cDNA species that comprisethe pool are tested individually (the pool is “broken down”) todetermine the specific cDNA that encodes a receptor able to interactwith the PRO polypeptide immunoadhesin.

In another embodiment of this assay, an epitope-tagged potential ligandPRO polypeptide (e.g. 8 histidine “His” tag) is allowed to interact witha panel of potential receptor PRO polypeptide molecules that have beenexpressed as fusions with the Fc domain of human IgG (immunoadhesins).Following a 1 hour co-incubation with the epitope tagged PROpolypeptide, the candidate receptors are each immunoprecipitated withprotein A beads and the beads are washed. Potential ligand interactionis determined by western blot analysis of the immunoprecipitatedcomplexes with antibody directed towards the epitope tag. An interactionis judged to occur if a band of the anticipated molecular weight of theepitope tagged protein is observed in the western blot analysis with acandidate receptor, but is not observed to occur with the other membersof the panel of potential receptors.

Using these assays, the following receptor/ligand interactions have beenherein identified: PRO245 binds to PRO1868.

The following materials have been deposited with the American TypeCulture Collection, 10801 University Boulevard, Manassas, VA USA (ATCC):Material ATCC Dep. No. Deposit Date DNA32292-1131 ATCC 209258 Sep. 16,1997 DNA33094-1131 ATCC 209256 Sep. 16, 1997 DNA33223-1136 ATCC 209264Sep. 16, 1997 DNA34435-1140 ATCC 209250 Sep. 16, 1997 DNA27864-1155 ATCC209375 Oct. 16, 1997 DNA36350-1158 ATCC 209378 Oct. 16, 1997DNA32290-1164 ATCC 209384 Oct. 16, 1997 DNA35639-1172 ATCC 209396 Oct.17, 1997 DNA33092-1202 ATCC 209420 Oct. 28, 1997 DNA49435-1219 ATCC209480 Nov. 21, 1997 DNA35638-1141 ATCC 209265 Sep. 16, 1997DNA32298-1132 ATCC 209257 Sep. 16, 1997 DNA33089-1132 ATCC 209262 Sep.16, 1997 DNA33786-1132 ATCC 209253 Sep. 16, 1997 DNA35918-1174 ATCC209402 Oct. 17, 1997 DNA37150-1178 ATCC 209401 Oct. 17, 1997DNA38260-1180 ATCC 209397 Oct. 17, 1997 DNA39969-1185 ATCC 209400 Oct.17, 1997 DNA32286-1191 ATCC 209385 Oct. 16, 1997 DNA33461-1199 ATCC209367 Oct. 15, 1997 DNA40628-1216 ATCC 209432 Nov. 7, 1997DNA33221-1133 ATCC 209263 Sep. 16, 1997 DNA33107-1135 ATCC 209251 Sep.16, 1997 DNA35557-1137 ATCC 209255 Sep. 16, 1997 DNA34434-1139 ATCC209252 Sep. 16, 1997 DNA33100-1159 ATCC 209373 Oct. 16, 1997DNA35600-1162 ATCC 209370 Oct. 16, 1997 DNA34436-1238 ATCC 209523 Dec.10, 1997 DNA33206-1165 ATCC 209372 Oct. 16, 1997 DNA35558-1167 ATCC209374 Oct. 16, 1997 DNA35599-1168 ATCC 209373 Oct. 16, 1997DNA36992-1168 ATCC 209382 Oct. 16, 1997 DNA34407-1169 ATCC 209383 Oct.16, 1997 DNA35841-1173 ATCC 209403 Oct. 17, 1997 DNA33470-1175 ATCC209398 Oct. 17, 1997 DNA34431-1177 ATCC 209399 Oct. 17, 1997DNA39510-1181 ATCC 209392 Oct. 17, 1997 DNA39423-1182 ATCC 209387 Oct.17, 1997 DNA40620-1183 ATCC 209388 Oct. 17, 1997 DNA40604-1187 ATCC209394 Oct. 17, 1997 DNA38268-1188 ATCC 209421 Oct. 28, 1997DNA37151-1193 ATCC 209393 Oct. 17, 1997 DNA35673-1201 ATCC 209418 Oct.28, 1997 DNA40370-1217 ATCC 209485 Nov. 21, 1997 DNA42551-1217 ATCC209483 Nov. 21, 1997 DNA39520-1217 ATCC 209482 Nov. 21, 1997DNA41225-1217 ATCC 209491 Nov. 21, 1997 DNA43318-1217 ATCC 209481 Nov.21, 1997 DNA40587-1231 ATCC 209438 Nov. 7, 1997 DNA41338-1234 ATCC209927 Jun. 2, 1998 DNA40981-1234 ATCC 209439 Nov. 7, 1997 DNA37140-1234ATCC 209489 Nov. 21, 1997 DNA40982-1235 ATCC 209433 Nov. 7, 1997DNA41379-1236 ATCC 209488 Nov. 21, 1997 DNA44167-1243 ATCC 209434 Nov.7, 1997 DNA39427-1179 ATCC 209395 Oct. 17, 1997 DNA40603-1232 ATCC209486 Nov. 21, 1997 DNA43466-1225 ATCC 209490 Nov. 21, 1997DNA43046-1225 ATCC 209484 Nov. 21, 1997 DNA35668-1171 ATCC 209371 Oct.16, 1997 DNA77624-2515 ATCC 203553 Dec. 22, 1998

These deposit were made under the provisions of the Budapest Treaty onthe International Recognition of the Deposit of Microorganisms for thePurpose of Patent Procedure and the Regulations thereunder (BudapestTreaty). This assures maintenance of a viable culture of the deposit for30 years from the date of deposit. The deposits will be made availableby ATCC under the terms of the Budapest Treaty, and subject to anagreement between Genentech, Inc. and ATCC, which assures that allrestrictions imposed by the depositor on the availability to the publicof the deposited material will be irrevocably removed upon the grantingof the pertinent U.S. patent, assures permanent and unrestrictedavailability of the progeny of the culture of the deposit to the publicupon issuance of the pertinent U.S. patent or upon laying open to thepublic of any U.S. or foreign patent application, whichever comes first,and assures availability of the progeny to one determined by the U.S.Commissioner of Patents and Trademarks to be entitled thereto accordingto 35 USC § 122 and the Commissioner's rules pursuant thereto (including37 CFR § 1.14 with particular reference to 886 OG 638).

The assignee of the present application has agreed that if a culture ofthe materials on deposit should die or be lost or destroyed whencultivated under suitable conditions, the materials will be promptlyreplaced on notification with another of the same. Availability of thedeposited material is not to be construed as a license to practice theinvention in contravention of the rights granted under the authority ofany government in accordance with its patent laws.

The foregoing written specification is considered to be sufficient toenable one skilled in the art to practice the invention. The presentinvention is not to be limited in scope by the construct deposited,since the deposited embodiment is intended as a single illustration ofcertain aspects of the invention and any constructs that arefunctionally equivalent are within the scope of this invention. Thedeposit of material herein does not constitute an admission that thewritten description herein contained is inadequate to enable thepractice of any aspect of the invention, including the best modethereof, nor is it to be construed as limiting the scope of the claimsto the specific illustrations that it represents. Indeed, variousmodifications of the invention in addition to those shown and describedherein will become apparent to those skilled in the art from theforegoing description and fall within the scope of the appended claims.

423 1 1825 DNA Homo sapiens 1 actgcacctc ggttctatcg attgaattccccggggatcc tctagagatc cctcgacctc 60 gacccacgcg tccgggccgg agcagcacggccgcaggacc tggagctccg gctgcgtctt 120 cccgcagcgc tacccgccat gcgcctgccgcgccgggccg cgctggggct cctgccgctt 180 ctgctgctgc tgccgcccgc gccggaggccgccaagaagc cgacgccctg ccaccggtgc 240 cgggggctgg tggacaagtt taaccaggggatggtggaca ccgcaaagaa gaactttggc 300 ggcgggaaca cggcttggga ggaaaagacgctgtccaagt acgagtccag cgagattcgc 360 ctgctggaga tcctggaggg gctgtgcgagagcagcgact tcgaatgcaa tcagatgcta 420 gaggcgcagg aggagcacct ggaggcctggtggctgcagc tgaagagcga atatcctgac 480 ttattcgagt ggttttgtgt gaagacactgaaagtgtgct gctctccagg aacctacggt 540 cccgactgtc tcgcatgcca gggcggatcccagaggccct gcagcgggaa tggccactgc 600 agcggagatg ggagcagaca gggcgacgggtcctgccggt gccacatggg gtaccagggc 660 ccgctgtgca ctgactgcat ggacggctacttcagctcgc tccggaacga gacccacagc 720 atctgcacag cctgtgacga gtcctgcaagacgtgctcgg gcctgaccaa cagagactgc 780 ggcgagtgtg aagtgggctg ggtgctggacgagggcgcct gtgtggatgt ggacgagtgt 840 gcggccgagc cgcctccctg cagcgctgcgcagttctgta agaacgccaa cggctcctac 900 acgtgcgaag agtgtgactc cagctgtgtgggctgcacag gggaaggccc aggaaactgt 960 aaagagtgta tctctggcta cgcgagggagcacggacagt gtgcagatgt ggacgagtgc 1020 tcactagcag aaaaaacctg tgtgaggaaaaacgaaaact gctacaatac tccagggagc 1080 tacgtctgtg tgtgtcctga cggcttcgaagaaacggaag atgcctgtgt gccgccggca 1140 gaggctgaag ccacagaagg agaaagcccgacacagctgc cctcccgcga agacctgtaa 1200 tgtgccggac ttacccttta aattattcagaaggatgtcc cgtggaaaat gtggccctga 1260 ggatgccgtc tcctgcagtg gacagcggcggggagaggct gcctgctctc taacggttga 1320 ttctcatttg tcccttaaac agctgcatttcttggttgtt cttaaacaga cttgtatatt 1380 ttgatacagt tctttgtaat aaaattgaccattgtaggta atcaggagga aaaaaaaaaa 1440 aaaaaaaaaa aaagggcggc cgcgactctagagtcgacct gcagaagctt ggccgccatg 1500 gcccaacttg tttattgcag cttataatggttacaaataa agcaatagca tcacaaattt 1560 cacaaataaa gcattttttt cactgcattctagttgtggt ttgtccaaac tcatcaatgt 1620 atcttatcat gtctggatcg ggaattaattcggcgcagca ccatggcctg aaataacctc 1680 tgaaagagga acttggttag gtaccttctgaggcggaaag aaccagctgt ggaatgtgtg 1740 tcagttaggg tgtggaaagt ccccaggctccccagcaggc agaagtatgc aagcatgcat 1800 ctcaattagt cagcaaccca gtttt 1825 2353 PRT Homo sapiens 2 Met Arg Leu Pro Arg Arg Ala Ala Leu Gly Leu LeuPro Leu Leu Leu 1 5 10 15 Leu Leu Pro Pro Ala Pro Glu Ala Ala Lys LysPro Thr Pro Cys His 20 25 30 Arg Cys Arg Gly Leu Val Asp Lys Phe Asn GlnGly Met Val Asp Thr 35 40 45 Ala Lys Lys Asn Phe Gly Gly Gly Asn Thr AlaTrp Glu Glu Lys Thr 50 55 60 Leu Ser Lys Tyr Glu Ser Ser Glu Ile Arg LeuLeu Glu Ile Leu Glu 65 70 75 80 Gly Leu Cys Glu Ser Ser Asp Phe Glu CysAsn Gln Met Leu Glu Ala 85 90 95 Gln Glu Glu His Leu Glu Ala Trp Trp LeuGln Leu Lys Ser Glu Tyr 100 105 110 Pro Asp Leu Phe Glu Trp Phe Cys ValLys Thr Leu Lys Val Cys Cys 115 120 125 Ser Pro Gly Thr Tyr Gly Pro AspCys Leu Ala Cys Gln Gly Gly Ser 130 135 140 Gln Arg Pro Cys Ser Gly AsnGly His Cys Ser Gly Asp Gly Ser Arg 145 150 155 160 Gln Gly Asp Gly SerCys Arg Cys His Met Gly Tyr Gln Gly Pro Leu 165 170 175 Cys Thr Asp CysMet Asp Gly Tyr Phe Ser Ser Leu Arg Asn Glu Thr 180 185 190 His Ser IleCys Thr Ala Cys Asp Glu Ser Cys Lys Thr Cys Ser Gly 195 200 205 Leu ThrAsn Arg Asp Cys Gly Glu Cys Glu Val Gly Trp Val Leu Asp 210 215 220 GluGly Ala Cys Val Asp Val Asp Glu Cys Ala Ala Glu Pro Pro Pro 225 230 235240 Cys Ser Ala Ala Gln Phe Cys Lys Asn Ala Asn Gly Ser Tyr Thr Cys 245250 255 Glu Glu Cys Asp Ser Ser Cys Val Gly Cys Thr Gly Glu Gly Pro Gly260 265 270 Asn Cys Lys Glu Cys Ile Ser Gly Tyr Ala Arg Glu His Gly GlnCys 275 280 285 Ala Asp Val Asp Glu Cys Ser Leu Ala Glu Lys Thr Cys ValArg Lys 290 295 300 Asn Glu Asn Cys Tyr Asn Thr Pro Gly Ser Tyr Val CysVal Cys Pro 305 310 315 320 Asp Gly Phe Glu Glu Thr Glu Asp Ala Cys ValPro Pro Ala Glu Ala 325 330 335 Glu Ala Thr Glu Gly Glu Ser Pro Thr GlnLeu Pro Ser Arg Glu Asp 340 345 350 Leu 3 2206 DNA Homo sapiens 3caggtccaac tgcacctcgg ttctatcgat tgaattcccc ggggatcctc tagagatccc 60tcgacctcga cccacgcgtc cgccaggccg ggaggcgacg cgcccagccg tctaaacggg 120aacagccctg gctgagggag ctgcagcgca gcagagtatc tgacggcgcc aggttgcgta 180ggtgcggcac gaggagtttt cccggcagcg aggaggtcct gagcagcatg gcccggagga 240gcgccttccc tgccgccgcg ctctggctct ggagcatcct cctgtgcctg ctggcactgc 300gggcggaggc cgggccgccg caggaggaga gcctgtacct atggatcgat gctcaccagg 360caagagtact cataggattt gaagaagata tcctgattgt ttcagagggg aaaatggcac 420cttttacaca tgatttcaga aaagcgcaac agagaatgcc agctattcct gtcaatatcc 480attccatgaa ttttacctgg caagctgcag ggcaggcaga atacttctat gaattcctgt 540ccttgcgctc cctggataaa ggcatcatgg cagatccaac cgtcaatgtc cctctgctgg 600gaacagtgcc tcacaaggca tcagttgttc aagttggttt cccatgtctt ggaaaacagg 660atggggtggc agcatttgaa gtggatgtga ttgttatgaa ttctgaaggc aacaccattc 720tccaaacacc tcaaaatgct atcttcttta aaacatgtca acaagctgag tgcccaggcg 780ggtgccgaaa tggaggcttt tgtaatgaaa gacgcatctg cgagtgtcct gatgggttcc 840acggacctca ctgtgagaaa gccctttgta ccccacgatg tatgaatggt ggactttgtg 900tgactcctgg tttctgcatc tgcccacctg gattctatgg agtgaactgt gacaaagcaa 960actgctcaac cacctgcttt aatggaggga cctgtttcta ccctggaaaa tgtatttgcc 1020ctccaggact agagggagag cagtgtgaaa tcagcaaatg cccacaaccc tgtcgaaatg 1080gaggtaaatg cattggtaaa agcaaatgta agtgttccaa aggttaccag ggagacctct 1140gttcaaagcc tgtctgcgag cctggctgtg gtgcacatgg aacctgccat gaacccaaca 1200aatgccaatg tcaagaaggt tggcatggaa gacactgcaa taaaaggtac gaagccagcc 1260tcatacatgc cctgaggcca gcaggcgccc agctcaggca gcacacgcct tcacttaaaa 1320aggccgagga gcggcgggat ccacctgaat ccaattacat ctggtgaact ccgacatctg 1380aaacgtttta agttacacca agttcatagc ctttgttaac ctttcatgtg ttgaatgttc 1440aaataatgtt cattacactt aagaatactg gcctgaattt tattagcttc attataaatc 1500actgagctga tatttactct tccttttaag ttttctaagt acgtctgtag catgatggta 1560tagattttct tgtttcagtg ctttgggaca gattttatat tatgtcaatt gatcaggtta 1620aaattttcag tgtgtagttg gcagatattt tcaaaattac aatgcattta tggtgtctgg 1680gggcagggga acatcagaaa ggttaaattg ggcaaaaatg cgtaagtcac aagaatttgg 1740atggtgcagt taatgttgaa gttacagcat ttcagatttt attgtcagat atttagatgt 1800ttgttacatt tttaaaaatt gctcttaatt tttaaactct caatacaata tattttgacc 1860ttaccattat tccagagatt cagtattaaa aaaaaaaaaa ttacactgtg gtagtggcat 1920ttaaacaata taatatattc taaacacaat gaaataggga atataatgta tgaacttttt 1980gcattggctt gaagcaatat aatatattgt aaacaaaaca cagctcttac ctaataaaca 2040ttttatactg tttgtatgta taaaataaag gtgctgcttt agttttttgg aaaaaaaaaa 2100aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa gggcggccgc gactctagag tcgacctgca 2160gaagcttggc cgccatggcc caacttgttt attgcagctt ataatg 2206 4 379 PRT Homosapiens 4 Met Ala Arg Arg Ser Ala Phe Pro Ala Ala Ala Leu Trp Leu TrpSer 1 5 10 15 Ile Leu Leu Cys Leu Leu Ala Leu Arg Ala Glu Ala Gly ProPro Gln 20 25 30 Glu Glu Ser Leu Tyr Leu Trp Ile Asp Ala His Gln Ala ArgVal Leu 35 40 45 Ile Gly Phe Glu Glu Asp Ile Leu Ile Val Ser Glu Gly LysMet Ala 50 55 60 Pro Phe Thr His Asp Phe Arg Lys Ala Gln Gln Arg Met ProAla Ile 65 70 75 80 Pro Val Asn Ile His Ser Met Asn Phe Thr Trp Gln AlaAla Gly Gln 85 90 95 Ala Glu Tyr Phe Tyr Glu Phe Leu Ser Leu Arg Ser LeuAsp Lys Gly 100 105 110 Ile Met Ala Asp Pro Thr Val Asn Val Pro Leu LeuGly Thr Val Pro 115 120 125 His Lys Ala Ser Val Val Gln Val Gly Phe ProCys Leu Gly Lys Gln 130 135 140 Asp Gly Val Ala Ala Phe Glu Val Asp ValIle Val Met Asn Ser Glu 145 150 155 160 Gly Asn Thr Ile Leu Gln Thr ProGln Asn Ala Ile Phe Phe Lys Thr 165 170 175 Cys Gln Gln Ala Glu Cys ProGly Gly Cys Arg Asn Gly Gly Phe Cys 180 185 190 Asn Glu Arg Arg Ile CysGlu Cys Pro Asp Gly Phe His Gly Pro His 195 200 205 Cys Glu Lys Ala LeuCys Thr Pro Arg Cys Met Asn Gly Gly Leu Cys 210 215 220 Val Thr Pro GlyPhe Cys Ile Cys Pro Pro Gly Phe Tyr Gly Val Asn 225 230 235 240 Cys AspLys Ala Asn Cys Ser Thr Thr Cys Phe Asn Gly Gly Thr Cys 245 250 255 PheTyr Pro Gly Lys Cys Ile Cys Pro Pro Gly Leu Glu Gly Glu Gln 260 265 270Cys Glu Ile Ser Lys Cys Pro Gln Pro Cys Arg Asn Gly Gly Lys Cys 275 280285 Ile Gly Lys Ser Lys Cys Lys Cys Ser Lys Gly Tyr Gln Gly Asp Leu 290295 300 Cys Ser Lys Pro Val Cys Glu Pro Gly Cys Gly Ala His Gly Thr Cys305 310 315 320 His Glu Pro Asn Lys Cys Gln Cys Gln Glu Gly Trp His GlyArg His 325 330 335 Cys Asn Lys Arg Tyr Glu Ala Ser Leu Ile His Ala LeuArg Pro Ala 340 345 350 Gly Ala Gln Leu Arg Gln His Thr Pro Ser Leu LysLys Ala Glu Glu 355 360 365 Arg Arg Asp Pro Pro Glu Ser Asn Tyr Ile Trp370 375 5 45 DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 5 agggagcacg gacagtgtgc agatgtggacgagtgctcac tagca 45 6 21 DNA Artificial Sequence Description ofArtificial Sequence Synthetic oligonucleotide probe 6 agagtgtatctctggctacg c 21 7 22 DNA Artificial Sequence Description of ArtificialSequence Synthetic oligonucleotide probe 7 taagtccggc acattacagg tc 22 849 DNA Artificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 8 cccacgatgt atgaatggtg gactttgtgt gactcctggtttctgcatc 49 9 22 DNA Artificial Sequence Description of ArtificialSequence Synthetic oligonucleotide probe 9 aaagacgcat ctgcgagtgt cc 2210 23 DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 10 tgctgatttc acactgctct ccc 23 11 2197DNA Homo sapiens 11 cggacgcgtg ggcgtccggc ggtcgcagag ccaggaggcggaggcgcgcg ggccagcctg 60 ggccccagcc cacaccttca ccagggccca ggagccaccatgtggcgatg tccactgggg 120 ctactgctgt tgctgccgct ggctggccac ttggctctgggtgcccagca gggtcgtggg 180 cgccgggagc tagcaccggg tctgcacctg cggggcatccgggacgcggg aggccggtac 240 tgccaggagc aggacctgtg ctgccgcggc cgtgccgacgactgtgccct gccctacctg 300 ggcgccatct gttactgtga cctcttctgc aaccgcacggtctccgactg ctgccctgac 360 ttctgggact tctgcctcgg cgtgccaccc ccttttcccccgatccaagg atgtatgcat 420 ggaggtcgta tctatccagt cttgggaacg tactgggacaactgtaaccg ttgcacctgc 480 caggagaaca ggcagtggca tggtggatcc agacatgatcaaagccatca accagggcaa 540 ctatggctgg caggctggga accacagcgc cttctggggcatgaccctgg atgagggcat 600 tcgctaccgc ctgggcacca tccgcccatc ttcctcggtcatgaacatgc atgaaattta 660 tacagtgctg aacccagggg aggtgcttcc cacagccttcgaggcctctg agaagtggcc 720 caacctgatt catgagcctc ttgaccaagg caactgtgcaggctcctggg ccttctccac 780 agcagctgtg gcatccgatc gtgtctcaat ccattctctgggacacatga cgcctgtcct 840 gtcgccccag aacctgctgt cttgtgacac ccaccagcagcagggctgcc gcggtgggcg 900 tctcgatggt gcctggtggt tcctgcgtcg ccgaggggtggtgtctgacc actgctaccc 960 cttctcgggc cgtgaacgag acgaggctgg ccctgcgcccccctgtatga tgcacagccg 1020 agccatgggt cggggcaagc gccaggccac tgcccactgccccaacagct atgttaataa 1080 caatgacatc taccaggtca ctcctgtcta ccgcctcggctccaacgaca aggagatcat 1140 gaaggagctg atggagaatg gccctgtcca agccctcatggaggtgcatg aggacttctt 1200 cctatacaag ggaggcatct acagccacac gccagtgagccttgggaggc cagagagata 1260 ccgccggcat gggacccact cagtcaagat cacaggatggggagaggaga cgctgccaga 1320 tggaaggacg ctcaaatact ggactgcggc caactcctggggcccagcct ggggcgagag 1380 gggccacttc cgcatcgtgc gcggcgtcaa tgagtgcgacatcgagagct tcgtgctggg 1440 cgtctggggc cgcgtgggca tggaggacat gggtcatcactgaggctgcg ggcaccacgc 1500 ggggtccggc ctgggatcca ggctaagggc cggcggaagaggccccaatg gggcggtgac 1560 cccagcctcg cccgacagag cccggggcgc aggcgggcgccagggcgcta atcccggcgc 1620 gggttccgct gacgcagcgc cccgcctggg agccgcgggcaggcgagact ggcggagccc 1680 ccagacctcc cagtggggac ggggcagggc ctggcctgggaagagcacag ctgcagatcc 1740 caggcctctg gcgcccccac tcaagactac caaagccaggacacctcaag tctccagccc 1800 caatacccca ccccaatccc gtattctttt ttttttttttttagacaggg tcttgctccg 1860 ttgcccaggt tggagtgcag tggcccatca gggctcactgtaacctccga ctcctgggtt 1920 caagtgaccc tcccacctca gcctctcaag tagctgggactacaggtgca ccaccacacc 1980 tggctaattt ttgtattttt tgtaaagagg ggggtctcactgtgttgccc aggctggttt 2040 cgaactcctg ggctcaagcg gtccacctgc ctccgcctcccaaagtgctg ggattgcagg 2100 catgagccac tgcacccagc cctgtattct tattcttcagatatttattt ttcttttcac 2160 tgttttaaaa taaaaccaaa gtattgataa aaaaaaa 219712 164 PRT Homo sapiens 12 Met Trp Arg Cys Pro Leu Gly Leu Leu Leu LeuLeu Pro Leu Ala Gly 1 5 10 15 His Leu Ala Leu Gly Ala Gln Gln Gly ArgGly Arg Arg Glu Leu Ala 20 25 30 Pro Gly Leu His Leu Arg Gly Ile Arg AspAla Gly Gly Arg Tyr Cys 35 40 45 Gln Glu Gln Asp Leu Cys Cys Arg Gly ArgAla Asp Asp Cys Ala Leu 50 55 60 Pro Tyr Leu Gly Ala Ile Cys Tyr Cys AspLeu Phe Cys Asn Arg Thr 65 70 75 80 Val Ser Asp Cys Cys Pro Asp Phe TrpAsp Phe Cys Leu Gly Val Pro 85 90 95 Pro Pro Phe Pro Pro Ile Gln Gly CysMet His Gly Gly Arg Ile Tyr 100 105 110 Pro Val Leu Gly Thr Tyr Trp AspAsn Cys Asn Arg Cys Thr Cys Gln 115 120 125 Glu Asn Arg Gln Trp His GlyGly Ser Arg His Asp Gln Ser His Gln 130 135 140 Pro Gly Gln Leu Trp LeuAla Gly Trp Glu Pro Gln Arg Leu Leu Gly 145 150 155 160 His Asp Pro Gly13 533 DNA Homo sapiens modified_base (33) a, t, c or g 13 aggctccttggccctttttc cacagcaagc ttntgcnatc ccgattcgtt gtctcaaatc 60 caattctcttgggacacatn acgcctgtcc tttngcccca gaacctgctg tcttgtacac 120 ccaccagcagcagggctgcc gcgntgggcg tctcgatggt gcctggtggt tcctgcgtcg 180 ccgagggntggtgtctgacc actgctaccc cttctcgggc cgtgaacgag acgaggctgg 240 ccctgcgcccccctgtatga tgcacagccg agccatgggt cggggcaagc gccaggccac 300 tgcccactgccccaacagct atgttaataa caatgacatc taccaggtca ctcctgtcta 360 ccgcctcggctccaacgaca aggagatcat gaaggagctg atggagaatg gccctgtcca 420 agccctcatggaggtgcatg aggacttctt cctatacaag ggaggcatct acagccacac 480 gccagtgagccttgggaggc cagagagata ccgccggcat gggacccact cag 533 14 24 DNA ArtificialSequence Description of Artificial Sequence Synthetic oligonucleotideprobe 14 ttcgaggcct ctgagaagtg gccc 24 15 22 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe 15ggcggtatct ctctggcctc cc 22 16 50 DNA Artificial Sequence Description ofArtificial Sequence Synthetic oligonucleotide probe 16 ttctccacagcagctgtggc atccgatcgt gtctcaatcc attctctggg 50 17 960 DNA Homo sapiens17 gctgcttgcc ctgttgatgg caggcttggc cctgcagcca ggcactgccc tgctgtgcta 60ctcctgcaaa gcccaggtga gcaacgagga ctgcctgcag gtggagaact gcacccagct 120gggggagcag tgctggaccg cgcgcatccg cgcagttggc ctcctgaccg tcatcagcaa 180aggctgcagc ttgaactgcg tggatgactc acaggactac tacgtgggca agaagaacat 240cacgtgctgt gacaccgact tgtgcaacgc cagcggggcc catgccctgc agccggctgc 300cgccatcctt gcgctgctcc ctgcactcgg cctgctgctc tggggacccg gccagctata 360ggctctgggg ggccccgctg cagcccacac tgggtgtggt gccccaggcc tctgtgccac 420tcctcacaga cctggcccag tgggagcctg tcctggttcc tgaggcacat cctaacgcaa 480gtctgaccat gtatgtctgc acccctgtcc cccaccctga ccctcccatg gccctctcca 540ggactcccac ccggcagatc agctctagtg acacagatcc gcctgcagat ggcccctcca 600accctctctg ctgctgtttc catggcccag cattctccac ccttaaccct gtgctcaggc 660acctcttccc ccaggaagcc ttccctgccc accccatcta tgacttgagc caggtctggt 720ccgtggtgtc ccccgcaccc agcaggggac aggcactcag gagggcccag taaaggctga 780gatgaagtgg actgagtaga actggaggac aagagtcgac gtgagttcct gggagtctcc 840agagatgggg cctggaggcc tggaggaagg ggccaggcct cacattcgtg gggctccctg 900aatggcagcc tgagcacagc gtaggccctt aataaacacc tgttggataa gccaaaaaaa 960 18189 PRT Homo sapiens 18 Met Thr His Arg Thr Thr Thr Trp Ala Arg Arg ThrSer Arg Ala Val 1 5 10 15 Thr Pro Thr Cys Ala Thr Pro Ala Gly Pro MetPro Cys Ser Arg Leu 20 25 30 Pro Pro Ser Leu Arg Cys Ser Leu His Ser AlaCys Cys Ser Gly Asp 35 40 45 Pro Ala Ser Tyr Arg Leu Trp Gly Ala Pro LeuGln Pro Thr Leu Gly 50 55 60 Val Val Pro Gln Ala Ser Val Pro Leu Leu ThrAsp Leu Ala Gln Trp 65 70 75 80 Glu Pro Val Leu Val Pro Glu Ala His ProAsn Ala Ser Leu Thr Met 85 90 95 Tyr Val Cys Thr Pro Val Pro His Pro AspPro Pro Met Ala Leu Ser 100 105 110 Arg Thr Pro Thr Arg Gln Ile Ser SerSer Asp Thr Asp Pro Pro Ala 115 120 125 Asp Gly Pro Ser Asn Pro Leu CysCys Cys Phe His Gly Pro Ala Phe 130 135 140 Ser Thr Leu Asn Pro Val LeuArg His Leu Phe Pro Gln Glu Ala Phe 145 150 155 160 Pro Ala His Pro IleTyr Asp Leu Ser Gln Val Trp Ser Val Val Ser 165 170 175 Pro Ala Pro SerArg Gly Gln Ala Leu Arg Arg Ala Gln 180 185 19 24 DNA ArtificialSequence Description of Artificial Sequence Synthetic oligonucleotideprobe 19 tgctgtgcta ctcctgcaaa gccc 24 20 24 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe 20tgcacaagtc ggtgtcacag cacg 24 21 44 DNA Artificial Sequence Descriptionof Artificial Sequence Synthetic oligonucleotide probe 21 agcaacgaggactgcctgca ggtggagaac tgcacccagc tggg 44 22 1200 DNA Homo sapiens 22cccacgcgtc cgaacctctc cagcgatggg agccgcccgc ctgctgccca acctcactct 60gtgcttacag ctgctgattc tctgctgtca aactcagtac gtgagggacc agggcgccat 120gaccgaccag ctgagcaggc ggcagatccg cgagtaccaa ctctacagca ggaccagtgg 180caagcacgtg caggtcaccg ggcgtcgcat ctccgccacc gccgaggacg gcaacaagtt 240tgccaagctc atagtggaga cggacacgtt tggcagccgg gttcgcatca aaggggctga 300gagtgagaag tacatctgta tgaacaagag gggcaagctc atcgggaagc ccagcgggaa 360gagcaaagac tgcgtgttca cggagatcgt gctggagaac aactatacgg ccttccagaa 420cgcccggcac gagggctggt tcatggcctt cacgcggcag gggcggcccc gccaggcttc 480ccgcagccgc cagaaccagc gcgaggccca cttcatcaag cgcctctacc aaggccagct 540gcccttcccc aaccacgccg agaagcagaa gcagttcgag tttgtgggct ccgcccccac 600ccgccggacc aagcgcacac ggcggcccca gcccctcacg tagtctggga ggcagggggc 660agcagcccct gggccgcctc cccacccctt tcccttctta atccaaggac tgggctgggg 720tggcgggagg ggagccagat ccccgaggga ggaccctgag ggccgcgaag catccgagcc 780cccagctggg aaggggcagg ccggtgcccc aggggcggct ggcacagtgc ccccttcccg 840gacgggtggc aggccctgga gaggaactga gtgtcaccct gatctcaggc caccagcctc 900tgccggcctc ccagccgggc tcctgaagcc cgctgaaagg tcagcgactg aaggccttgc 960agacaaccgt ctggaggtgg ctgtcctcaa aatctgcttc tcggatctcc ctcagtctgc 1020ccccagcccc caaactcctc ctggctagac tgtaggaagg gacttttgtt tgtttgtttg 1080tttcaggaaa aaagaaaggg agagagagga aaatagaggg ttgtccactc ctcacattcc 1140acgacccagg cctgcacccc acccccaact cccagccccg gaataaaacc attttcctgc 120023 205 PRT Homo sapiens 23 Met Gly Ala Ala Arg Leu Leu Pro Asn Leu ThrLeu Cys Leu Gln Leu 1 5 10 15 Leu Ile Leu Cys Cys Gln Thr Gln Tyr ValArg Asp Gln Gly Ala Met 20 25 30 Thr Asp Gln Leu Ser Arg Arg Gln Ile ArgGlu Tyr Gln Leu Tyr Ser 35 40 45 Arg Thr Ser Gly Lys His Val Gln Val ThrGly Arg Arg Ile Ser Ala 50 55 60 Thr Ala Glu Asp Gly Asn Lys Phe Ala LysLeu Ile Val Glu Thr Asp 65 70 75 80 Thr Phe Gly Ser Arg Val Arg Ile LysGly Ala Glu Ser Glu Lys Tyr 85 90 95 Ile Cys Met Asn Lys Arg Gly Lys LeuIle Gly Lys Pro Ser Gly Lys 100 105 110 Ser Lys Asp Cys Val Phe Thr GluIle Val Leu Glu Asn Asn Tyr Thr 115 120 125 Ala Phe Gln Asn Ala Arg HisGlu Gly Trp Phe Met Ala Phe Thr Arg 130 135 140 Gln Gly Arg Pro Arg GlnAla Ser Arg Ser Arg Gln Asn Gln Arg Glu 145 150 155 160 Ala His Phe IleLys Arg Leu Tyr Gln Gly Gln Leu Pro Phe Pro Asn 165 170 175 His Ala GluLys Gln Lys Gln Phe Glu Phe Val Gly Ser Ala Pro Thr 180 185 190 Arg ArgThr Lys Arg Thr Arg Arg Pro Gln Pro Leu Thr 195 200 205 24 28 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 24 cagtacgtga gggaccaggg cgccatga 28 25 24 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 25 ccggtgacct gcacgtgctt gcca 24 26 41 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 26 gcggatctgc cgcctgctca nctggtcggt catggcgccc t41 27 2479 DNA Homo sapiens 27 acttgccatc acctgttgcc agtgtggaaaaattctccct gttgaatttt ttgcacatgg 60 aggacagcag caaagagggc aacacaggctgataagacca gagacagcag ggagattatt 120 ttaccatacg ccctcaggac gttccctctagctggagttc tggacttcaa cagaacccca 180 tccagtcatt ttgattttgc tgtttattttttttttcttt ttctttttcc caccacattg 240 tattttattt ccgtacttca gaaatgggcctacagaccac aaagtggccc agccatgggg 300 cttttttcct gaagtcttgg cttatcatttccctggggct ctactcacag gtgtccaaac 360 tcctggcctg ccctagtgtg tgccgctgcgacaggaactt tgtctactgt aatgagcgaa 420 gcttgacctc agtgcctctt gggatcccggagggcgtaac cgtactctac ctccacaaca 480 accaaattaa taatgctgga tttcctgcagaactgcacaa tgtacagtcg gtgcacacgg 540 tctacctgta tggcaaccaa ctggacgaattccccatgaa ccttcccaag aatgtcagag 600 ttctccattt gcaggaaaac aatattcagaccatttcacg ggctgctctt gcccagctct 660 tgaagcttga agagctgcac ctggatgacaactccatatc cacagtgggg gtggaagacg 720 gggccttccg ggaggctatt agcctcaaattgttgttttt gtctaagaat cacctgagca 780 gtgtgcctgt tgggcttcct gtggacttgcaagagctgag agtggatgaa aatcgaattg 840 ctgtcatatc cgacatggcc ttccagaatctcacgagctt ggagcgtctt attgtggacg 900 ggaacctcct gaccaacaag ggtatcgccgagggcacctt cagccatctc accaagctca 960 aggaattttc aattgtacgt aattcgctgtcccaccctcc tcccgatctc ccaggtacgc 1020 atctgatcag gctctatttg caggacaaccagataaacca cattcctttg acagccttct 1080 caaatctgcg taagctggaa cggctggatatatccaacaa ccaactgcgg atgctgactc 1140 aaggggtttt tgataatctc tccaacctgaagcagctcac tgctcggaat aacccttggt 1200 tttgtgactg cagtattaaa tgggtcacagaatggctcaa atatatccct tcatctctca 1260 acgtgcgggg tttcatgtgc caaggtcctgaacaagtccg ggggatggcc gtcagggaat 1320 taaatatgaa tcttttgtcc tgtcccaccacgacccccgg cctgcctctc ttcaccccag 1380 ccccaagtac agcttctccg accactcagcctcccaccct ctctattcca aaccctagca 1440 gaagctacac gcctccaact cctaccacatcgaaacttcc cacgattcct gactgggatg 1500 gcagagaaag agtgacccca cctatttctgaacggatcca gctctctatc cattttgtga 1560 atgatacttc cattcaagtc agctggctctctctcttcac cgtgatggca tacaaactca 1620 catgggtgaa aatgggccac agtttagtagggggcatcgt tcaggagcgc atagtcagcg 1680 gtgagaagca acacctgagc ctggttaacttagagccccg atccacctat cggatttgtt 1740 tagtgccact ggatgctttt aactaccgcgcggtagaaga caccatttgt tcagaggcca 1800 ccacccatgc ctcctatctg aacaacggcagcaacacagc gtccagccat gagcagacga 1860 cgtcccacag catgggctcc ccctttctgctggcgggctt gatcgggggc gcggtgatat 1920 ttgtgctggt ggtcttgctc agcgtcttttgctggcatat gcacaaaaag gggcgctaca 1980 cctcccagaa gtggaaatac aaccggggccggcggaaaga tgattattgc gaggcaggca 2040 ccaagaagga caactccatc ctggagatgacagaaaccag ttttcagatc gtctccttaa 2100 ataacgatca actccttaaa ggagatttcagactgcagcc catttacacc ccaaatgggg 2160 gcattaatta cacagactgc catatccccaacaacatgcg atactgcaac agcagcgtgc 2220 cagacctgga gcactgccat acgtgacagccagaggccca gcgttatcaa ggcggacaat 2280 tagactcttg agaacacact cgtgtgtgcacataaagaca cgcagattac atttgataaa 2340 tgttacacag atgcatttgt gcatttgaatactctgtaat ttatacggtg tactatataa 2400 tgggatttaa aaaaagtgct atcttttctatttcaagtta attacaaaca gttttgtaac 2460 tctttgcttt ttaaatctt 2479 28 660PRT Homo sapiens 28 Met Gly Leu Gln Thr Thr Lys Trp Pro Ser His Gly AlaPhe Phe Leu 1 5 10 15 Lys Ser Trp Leu Ile Ile Ser Leu Gly Leu Tyr SerGln Val Ser Lys 20 25 30 Leu Leu Ala Cys Pro Ser Val Cys Arg Cys Asp ArgAsn Phe Val Tyr 35 40 45 Cys Asn Glu Arg Ser Leu Thr Ser Val Pro Leu GlyIle Pro Glu Gly 50 55 60 Val Thr Val Leu Tyr Leu His Asn Asn Gln Ile AsnAsn Ala Gly Phe 65 70 75 80 Pro Ala Glu Leu His Asn Val Gln Ser Val HisThr Val Tyr Leu Tyr 85 90 95 Gly Asn Gln Leu Asp Glu Phe Pro Met Asn LeuPro Lys Asn Val Arg 100 105 110 Val Leu His Leu Gln Glu Asn Asn Ile GlnThr Ile Ser Arg Ala Ala 115 120 125 Leu Ala Gln Leu Leu Lys Leu Glu GluLeu His Leu Asp Asp Asn Ser 130 135 140 Ile Ser Thr Val Gly Val Glu AspGly Ala Phe Arg Glu Ala Ile Ser 145 150 155 160 Leu Lys Leu Leu Phe LeuSer Lys Asn His Leu Ser Ser Val Pro Val 165 170 175 Gly Leu Pro Val AspLeu Gln Glu Leu Arg Val Asp Glu Asn Arg Ile 180 185 190 Ala Val Ile SerAsp Met Ala Phe Gln Asn Leu Thr Ser Leu Glu Arg 195 200 205 Leu Ile ValAsp Gly Asn Leu Leu Thr Asn Lys Gly Ile Ala Glu Gly 210 215 220 Thr PheSer His Leu Thr Lys Leu Lys Glu Phe Ser Ile Val Arg Asn 225 230 235 240Ser Leu Ser His Pro Pro Pro Asp Leu Pro Gly Thr His Leu Ile Arg 245 250255 Leu Tyr Leu Gln Asp Asn Gln Ile Asn His Ile Pro Leu Thr Ala Phe 260265 270 Ser Asn Leu Arg Lys Leu Glu Arg Leu Asp Ile Ser Asn Asn Gln Leu275 280 285 Arg Met Leu Thr Gln Gly Val Phe Asp Asn Leu Ser Asn Leu LysGln 290 295 300 Leu Thr Ala Arg Asn Asn Pro Trp Phe Cys Asp Cys Ser IleLys Trp 305 310 315 320 Val Thr Glu Trp Leu Lys Tyr Ile Pro Ser Ser LeuAsn Val Arg Gly 325 330 335 Phe Met Cys Gln Gly Pro Glu Gln Val Arg GlyMet Ala Val Arg Glu 340 345 350 Leu Asn Met Asn Leu Leu Ser Cys Pro ThrThr Thr Pro Gly Leu Pro 355 360 365 Leu Phe Thr Pro Ala Pro Ser Thr AlaSer Pro Thr Thr Gln Pro Pro 370 375 380 Thr Leu Ser Ile Pro Asn Pro SerArg Ser Tyr Thr Pro Pro Thr Pro 385 390 395 400 Thr Thr Ser Lys Leu ProThr Ile Pro Asp Trp Asp Gly Arg Glu Arg 405 410 415 Val Thr Pro Pro IleSer Glu Arg Ile Gln Leu Ser Ile His Phe Val 420 425 430 Asn Asp Thr SerIle Gln Val Ser Trp Leu Ser Leu Phe Thr Val Met 435 440 445 Ala Tyr LysLeu Thr Trp Val Lys Met Gly His Ser Leu Val Gly Gly 450 455 460 Ile ValGln Glu Arg Ile Val Ser Gly Glu Lys Gln His Leu Ser Leu 465 470 475 480Val Asn Leu Glu Pro Arg Ser Thr Tyr Arg Ile Cys Leu Val Pro Leu 485 490495 Asp Ala Phe Asn Tyr Arg Ala Val Glu Asp Thr Ile Cys Ser Glu Ala 500505 510 Thr Thr His Ala Ser Tyr Leu Asn Asn Gly Ser Asn Thr Ala Ser Ser515 520 525 His Glu Gln Thr Thr Ser His Ser Met Gly Ser Pro Phe Leu LeuAla 530 535 540 Gly Leu Ile Gly Gly Ala Val Ile Phe Val Leu Val Val LeuLeu Ser 545 550 555 560 Val Phe Cys Trp His Met His Lys Lys Gly Arg TyrThr Ser Gln Lys 565 570 575 Trp Lys Tyr Asn Arg Gly Arg Arg Lys Asp AspTyr Cys Glu Ala Gly 580 585 590 Thr Lys Lys Asp Asn Ser Ile Leu Glu MetThr Glu Thr Ser Phe Gln 595 600 605 Ile Val Ser Leu Asn Asn Asp Gln LeuLeu Lys Gly Asp Phe Arg Leu 610 615 620 Gln Pro Ile Tyr Thr Pro Asn GlyGly Ile Asn Tyr Thr Asp Cys His 625 630 635 640 Ile Pro Asn Asn Met ArgTyr Cys Asn Ser Ser Val Pro Asp Leu Glu 645 650 655 His Cys His Thr 66029 21 DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 29 cggtctacct gtatggcaac c 21 30 22 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 30 gcaggacaac cagataaacc ac 22 31 22 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 31 acgcagattt gagaaggctg tc 22 32 46 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 32 ttcacgggct gctcttgccc agctcttgaa gcttgaagagctgcac 46 33 3449 DNA Homo sapiens 33 acttggagca agcggcggcg gcggagacagaggcagaggc agaagctggg gctccgtcct 60 cgcctcccac gagcgatccc cgaggagagccgcggccctc ggcgaggcga agaggccgac 120 gaggaagacc cgggtggctg cgcccctgcctcgcttccca ggcgccggcg gctgcagcct 180 tgcccctctt gctcgccttg aaaatggaaaagatgctcgc aggctgcttt ctgctgatcc 240 tcggacagat cgtcctcctc cctgccgaggccagggagcg gtcacgtggg aggtccatct 300 ctaggggcag acacgctcgg acccacccgcagacggccct tctggagagt tcctgtgaga 360 acaagcgggc agacctggtt ttcatcattgacagctctcg cagtgtcaac acccatgact 420 atgcaaaggt caaggagttc atcgtggacatcttgcaatt cttggacatt ggtcctgatg 480 tcacccgagt gggcctgctc caatatggcagcactgtcaa gaatgagttc tccctcaaga 540 ccttcaagag gaagtccgag gtggagcgtgctgtcaagag gatgcggcat ctgtccacgg 600 gcaccatgac tgggctggcc atccagtatgccctgaacat cgcattctca gaagcagagg 660 gggcccggcc cctgagggag aatgtgccacgggtcataat gatcgtgaca gatgggagac 720 ctcaggactc cgtggccgag gtggctgctaaggcacggga cacgggcatc ctaatctttg 780 ccattggtgt gggccaggta gacttcaacaccttgaagtc cattgggagt gagccccatg 840 aggaccatgt cttccttgtg gccaatttcagccagattga gacgctgacc tccgtgttcc 900 agaagaagtt gtgcacggcc cacatgtgcagcaccctgga gcataactgt gcccacttct 960 gcatcaacat ccctggctca tacgtctgcaggtgcaaaca aggctacatt ctcaactcgg 1020 atcagacgac ttgcagaatc caggatctgtgtgccatgga ggaccacaac tgtgagcagc 1080 tctgtgtgaa tgtgccgggc tccttcgtctgccagtgcta cagtggctac gccctggctg 1140 aggatgggaa gaggtgtgtg gctgtggactactgtgcctc agaaaaccac ggatgtgaac 1200 atgagtgtgt aaatgctgat ggctcctacctttgccagtg ccatgaagga tttgctctta 1260 acccagatga aaaaacgtgc acaaggatcaactactgtgc actgaacaaa ccgggctgtg 1320 agcatgagtg cgtcaacatg gaggagagctactactgccg ctgccaccgt ggctacactc 1380 tggaccccaa tggcaaaacc tgcagccgagtggaccactg tgcacagcag gaccatggct 1440 gtgagcagct gtgtctgaac acggaggattccttcgtctg ccagtgctca gaaggcttcc 1500 tcatcaacga ggacctcaag acctgctcccgggtggatta ctgcctgctg agtgaccatg 1560 gttgtgaata ctcctgtgtc aacatggacagatcctttgc ctgtcagtgt cctgagggac 1620 acgtgctccg cagcgatggg aagacgtgtgcaaaattgga ctcttgtgct ctgggggacc 1680 acggttgtga acattcgtgt gtaagcagtgaagattcgtt tgtgtgccag tgctttgaag 1740 gttatatact ccgtgaagat ggaaaaacctgcagaaggaa agatgtctgc caagctatag 1800 accatggctg tgaacacatt tgtgtgaacagtgacgactc atacacgtgc gagtgcttgg 1860 agggattccg gctcgctgag gatgggaaacgctgccgaag gaaggatgtc tgcaaatcaa 1920 cccaccatgg ctgcgaacac atttgtgttaataatgggaa ttcctacatc tgcaaatgct 1980 cagagggatt tgttctagct gaggacggaagacggtgcaa gaaatgcact gaaggcccaa 2040 ttgacctggt ctttgtgatc gatggatccaagagtcttgg agaagagaat tttgaggtcg 2100 tgaagcagtt tgtcactgga attatagattccttgacaat ttcccccaaa gccgctcgag 2160 tggggctgct ccagtattcc acacaggtccacacagagtt cactctgaga aacttcaact 2220 cagccaaaga catgaaaaaa gccgtggcccacatgaaata catgggaaag ggctctatga 2280 ctgggctggc cctgaaacac atgtttgagagaagttttac ccaaggagaa ggggccaggc 2340 ccctttccac aagggtgccc agagcagccattgtgttcac cgacggacgg gctcaggatg 2400 acgtctccga gtgggccagt aaagccaaggccaatggtat cactatgtat gctgttgggg 2460 taggaaaagc cattgaggag gaactacaagagattgcctc tgagcccaca aacaagcatc 2520 tcttctatgc cgaagacttc agcacaatggatgagataag tgaaaaactc aagaaaggca 2580 tctgtgaagc tctagaagac tccgatggaagacaggactc tccagcaggg gaactgccaa 2640 aaacggtcca acagccaaca gaatctgagccagtcaccat aaatatccaa gacctacttt 2700 cctgttctaa ttttgcagtg caacacagatatctgtttga agaagacaat cttttacggt 2760 ctacacaaaa gctttcccat tcaacaaaaccttcaggaag ccctttggaa gaaaaacacg 2820 atcaatgcaa atgtgaaaac cttataatgttccagaacct tgcaaacgaa gaagtaagaa 2880 aattaacaca gcgcttagaa gaaatgacacagagaatgga agccctggaa aatcgcctga 2940 gatacagatg aagattagaa atcgcgacacatttgtagtc attgtatcac ggattacaat 3000 gaacgcagtg cagagcccca aagctcaggctattgttaaa tcaataatgt tgtgaagtaa 3060 aacaatcagt actgagaaac ctggtttgccacagaacaaa gacaagaagt atacactaac 3120 ttgtataaat ttatctagga aaaaaatccttcagaattct aagatgaatt taccaggtga 3180 gaatgaataa gctatgcaag gtattttgtaatatactgtg gacacaactt gcttctgcct 3240 catcctgcct tagtgtgcaa tctcatttgactatacgata aagtttgcac agtcttactt 3300 ctgtagaaca ctggccatag gaaatgctgtttttttgtac tggactttac cttgatatat 3360 gtatatggat gtatgcataa aatcataggacatatgtact tgtggaacaa gttggatttt 3420 ttatacaata ttaaaattca ccacttcag3449 34 915 PRT Homo sapiens 34 Met Glu Lys Met Leu Ala Gly Cys Phe LeuLeu Ile Leu Gly Gln Ile 1 5 10 15 Val Leu Leu Pro Ala Glu Ala Arg GluArg Ser Arg Gly Arg Ser Ile 20 25 30 Ser Arg Gly Arg His Ala Arg Thr HisPro Gln Thr Ala Leu Leu Glu 35 40 45 Ser Ser Cys Glu Asn Lys Arg Ala AspLeu Val Phe Ile Ile Asp Ser 50 55 60 Ser Arg Ser Val Asn Thr His Asp TyrAla Lys Val Lys Glu Phe Ile 65 70 75 80 Val Asp Ile Leu Gln Phe Leu AspIle Gly Pro Asp Val Thr Arg Val 85 90 95 Gly Leu Leu Gln Tyr Gly Ser ThrVal Lys Asn Glu Phe Ser Leu Lys 100 105 110 Thr Phe Lys Arg Lys Ser GluVal Glu Arg Ala Val Lys Arg Met Arg 115 120 125 His Leu Ser Thr Gly ThrMet Thr Gly Leu Ala Ile Gln Tyr Ala Leu 130 135 140 Asn Ile Ala Phe SerGlu Ala Glu Gly Ala Arg Pro Leu Arg Glu Asn 145 150 155 160 Val Pro ArgVal Ile Met Ile Val Thr Asp Gly Arg Pro Gln Asp Ser 165 170 175 Val AlaGlu Val Ala Ala Lys Ala Arg Asp Thr Gly Ile Leu Ile Phe 180 185 190 AlaIle Gly Val Gly Gln Val Asp Phe Asn Thr Leu Lys Ser Ile Gly 195 200 205Ser Glu Pro His Glu Asp His Val Phe Leu Val Ala Asn Phe Ser Gln 210 215220 Ile Glu Thr Leu Thr Ser Val Phe Gln Lys Lys Leu Cys Thr Ala His 225230 235 240 Met Cys Ser Thr Leu Glu His Asn Cys Ala His Phe Cys Ile AsnIle 245 250 255 Pro Gly Ser Tyr Val Cys Arg Cys Lys Gln Gly Tyr Ile LeuAsn Ser 260 265 270 Asp Gln Thr Thr Cys Arg Ile Gln Asp Leu Cys Ala MetGlu Asp His 275 280 285 Asn Cys Glu Gln Leu Cys Val Asn Val Pro Gly SerPhe Val Cys Gln 290 295 300 Cys Tyr Ser Gly Tyr Ala Leu Ala Glu Asp GlyLys Arg Cys Val Ala 305 310 315 320 Val Asp Tyr Cys Ala Ser Glu Asn HisGly Cys Glu His Glu Cys Val 325 330 335 Asn Ala Asp Gly Ser Tyr Leu CysGln Cys His Glu Gly Phe Ala Leu 340 345 350 Asn Pro Asp Glu Lys Thr CysThr Arg Ile Asn Tyr Cys Ala Leu Asn 355 360 365 Lys Pro Gly Cys Glu HisGlu Cys Val Asn Met Glu Glu Ser Tyr Tyr 370 375 380 Cys Arg Cys His ArgGly Tyr Thr Leu Asp Pro Asn Gly Lys Thr Cys 385 390 395 400 Ser Arg ValAsp His Cys Ala Gln Gln Asp His Gly Cys Glu Gln Leu 405 410 415 Cys LeuAsn Thr Glu Asp Ser Phe Val Cys Gln Cys Ser Glu Gly Phe 420 425 430 LeuIle Asn Glu Asp Leu Lys Thr Cys Ser Arg Val Asp Tyr Cys Leu 435 440 445Leu Ser Asp His Gly Cys Glu Tyr Ser Cys Val Asn Met Asp Arg Ser 450 455460 Phe Ala Cys Gln Cys Pro Glu Gly His Val Leu Arg Ser Asp Gly Lys 465470 475 480 Thr Cys Ala Lys Leu Asp Ser Cys Ala Leu Gly Asp His Gly CysGlu 485 490 495 His Ser Cys Val Ser Ser Glu Asp Ser Phe Val Cys Gln CysPhe Glu 500 505 510 Gly Tyr Ile Leu Arg Glu Asp Gly Lys Thr Cys Arg ArgLys Asp Val 515 520 525 Cys Gln Ala Ile Asp His Gly Cys Glu His Ile CysVal Asn Ser Asp 530 535 540 Asp Ser Tyr Thr Cys Glu Cys Leu Glu Gly PheArg Leu Ala Glu Asp 545 550 555 560 Gly Lys Arg Cys Arg Arg Lys Asp ValCys Lys Ser Thr His His Gly 565 570 575 Cys Glu His Ile Cys Val Asn AsnGly Asn Ser Tyr Ile Cys Lys Cys 580 585 590 Ser Glu Gly Phe Val Leu AlaGlu Asp Gly Arg Arg Cys Lys Lys Cys 595 600 605 Thr Glu Gly Pro Ile AspLeu Val Phe Val Ile Asp Gly Ser Lys Ser 610 615 620 Leu Gly Glu Glu AsnPhe Glu Val Val Lys Gln Phe Val Thr Gly Ile 625 630 635 640 Ile Asp SerLeu Thr Ile Ser Pro Lys Ala Ala Arg Val Gly Leu Leu 645 650 655 Gln TyrSer Thr Gln Val His Thr Glu Phe Thr Leu Arg Asn Phe Asn 660 665 670 SerAla Lys Asp Met Lys Lys Ala Val Ala His Met Lys Tyr Met Gly 675 680 685Lys Gly Ser Met Thr Gly Leu Ala Leu Lys His Met Phe Glu Arg Ser 690 695700 Phe Thr Gln Gly Glu Gly Ala Arg Pro Leu Ser Thr Arg Val Pro Arg 705710 715 720 Ala Ala Ile Val Phe Thr Asp Gly Arg Ala Gln Asp Asp Val SerGlu 725 730 735 Trp Ala Ser Lys Ala Lys Ala Asn Gly Ile Thr Met Tyr AlaVal Gly 740 745 750 Val Gly Lys Ala Ile Glu Glu Glu Leu Gln Glu Ile AlaSer Glu Pro 755 760 765 Thr Asn Lys His Leu Phe Tyr Ala Glu Asp Phe SerThr Met Asp Glu 770 775 780 Ile Ser Glu Lys Leu Lys Lys Gly Ile Cys GluAla Leu Glu Asp Ser 785 790 795 800 Asp Gly Arg Gln Asp Ser Pro Ala GlyGlu Leu Pro Lys Thr Val Gln 805 810 815 Gln Pro Thr Glu Ser Glu Pro ValThr Ile Asn Ile Gln Asp Leu Leu 820 825 830 Ser Cys Ser Asn Phe Ala ValGln His Arg Tyr Leu Phe Glu Glu Asp 835 840 845 Asn Leu Leu Arg Ser ThrGln Lys Leu Ser His Ser Thr Lys Pro Ser 850 855 860 Gly Ser Pro Leu GluGlu Lys His Asp Gln Cys Lys Cys Glu Asn Leu 865 870 875 880 Ile Met PheGln Asn Leu Ala Asn Glu Glu Val Arg Lys Leu Thr Gln 885 890 895 Arg LeuGlu Glu Met Thr Gln Arg Met Glu Ala Leu Glu Asn Arg Leu 900 905 910 ArgTyr Arg 915 35 23 DNA Artificial Sequence Description of ArtificialSequence Synthetic oligonucleotide probe 35 gtgaccctgg ttgtgaatac tcc 2336 22 DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 36 acagccatgg tctatagctt gg 22 37 45 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 37 gcctgtcagt gtcctgaggg acacgtgctc cgcagcgatgggaag 45 38 1813 DNA Homo sapiens 38 ggagccgccc tgggtgtcag cggctcggctcccgcgcacg ctccggccgt cgcgcagcct 60 cggcacctgc aggtccgtgc gtcccgcggctggcgcccct gactccgtcc cggccaggga 120 gggccatgat ttccctcccg gggcccctggtgaccaactt gctgcggttt ttgttcctgg 180 ggctgagtgc cctcgcgccc ccctcgcgggcccagctgca actgcacttg cccgccaacc 240 ggttgcaggc ggtggaggga ggggaagtggtgcttccagc gtggtacacc ttgcacgggg 300 aggtgtcttc atcccagcca tgggaggtgccctttgtgat gtggttcttc aaacagaaag 360 aaaaggagga tcaggtgttg tcctacatcaatggggtcac aacaagcaaa cctggagtat 420 ccttggtcta ctccatgccc tcccggaacctgtccctgcg gctggagggt ctccaggaga 480 aagactctgg cccctacagc tgctccgtgaatgtgcaaga caaacaaggc aaatctaggg 540 gccacagcat caaaacctta gaactcaatgtactggttcc tccagctcct ccatcctgcc 600 gtctccaggg tgtgccccat gtgggggcaaacgtgaccct gagctgccag tctccaagga 660 gtaagcccgc tgtccaatac cagtgggatcggcagcttcc atccttccag actttctttg 720 caccagcatt agatgtcatc cgtgggtctttaagcctcac caacctttcg tcttccatgg 780 ctggagtcta tgtctgcaag gcccacaatgaggtgggcac tgcccaatgt aatgtgacgc 840 tggaagtgag cacagggcct ggagctgcagtggttgctgg agctgttgtg ggtaccctgg 900 ttggactggg gttgctggct gggctggtcctcttgtacca ccgccggggc aaggccctgg 960 aggagccagc caatgatatc aaggaggatgccattgctcc ccggaccctg ccctggccca 1020 tccggccacc ccatggccct cccaggcctggtgcattgac ccccacgccc agtctctcca 1140 cccccatccc tggtggggtt tcttcctctggcttgagccg catgggtgct gtgcctgtga 1260 aaggatttgg ggtctctcct tcctataagggtcacctcta gcacagaggc ctgagtcatg 1380 accatctcag taagacctaa gtgtccaggagacagaagga gaagaggaag tggatctgga 1500 ctactcacca agagtgaggg gcagagacttccagtcactg agtctcccag gcccccttga 1620 ataacctgtc aggctggctt ggttaggttttactggggca gaggataggg aatctcttat 1740 tttgtatgaa aaa 1813 39 390 PRTHomo sapiens 39 Met Ile Ser Leu Pro Gly Pro Leu Val Thr Asn Leu Leu ArgPhe Leu 1 5 10 15 Phe Leu Gly Leu Ser Ala Leu Ala Pro Pro Ser Arg AlaGln Leu Gln 20 25 30 Leu His Leu Pro Ala Asn Arg Leu Gln Ala Val Glu GlyGly Glu Val 35 40 45 Val Leu Pro Ala Trp Tyr Thr Leu His Gly Glu Val SerSer Ser Gln 50 55 60 Pro Trp Glu Val Pro Phe Val Met Trp Phe Phe Lys GlnLys Glu Lys 65 70 75 80 Glu Asp Gln Val Leu Ser Tyr Ile Asn Gly Val ThrThr Ser Lys Pro 85 90 95 Gly Val Ser Leu Val Tyr Ser Met Pro Ser Arg AsnLeu Ser Leu Arg 100 105 110 Leu Glu Gly Leu Gln Glu Lys Asp Ser Gly ProTyr Ser Cys Ser Val 115 120 125 Asn Val Gln Asp Lys Gln Gly Lys Ser ArgGly His Ser Ile Lys Thr 130 135 140 Leu Glu Leu Asn Val Leu Val Pro ProAla Pro Pro Ser Cys Arg Leu 145 150 155 160 Gln Gly Val Pro His Val GlyAla Asn Val Thr Leu Ser Cys Gln Ser 165 170 175 Pro Arg Ser Lys Pro AlaVal Gln Tyr Gln Trp Asp Arg Gln Leu Pro 180 185 190 Ser Phe Gln Thr PhePhe Ala Pro Ala Leu Asp Val Ile Arg Gly Ser 195 200 205 Leu Ser Leu ThrAsn Leu Ser Ser Ser Met Ala Gly Val Tyr Val Cys 210 215 220 Lys Ala HisAsn Glu Val Gly Thr Ala Gln Cys Asn Val Thr Leu Glu 225 230 235 240 ValSer Thr Gly Pro Gly Ala Ala Val Val Ala Gly Ala Val Val Gly 245 250 255Thr Leu Val Gly Leu Gly Leu Leu Ala Gly Leu Val Leu Leu Tyr His 260 265270 Arg Arg Gly Lys Ala Leu Glu Glu Pro Ala Asn Asp Ile Lys Glu Asp 275280 285 Ala Ile Ala Pro Arg Thr Leu Pro Trp Pro Lys Ser Ser Asp Thr Ile290 295 300 Ser Lys Asn Gly Thr Leu Ser Ser Val Thr Ser Ala Arg Ala LeuArg 305 310 315 320 Pro Pro His Gly Pro Pro Arg Pro Gly Ala Leu Thr ProThr Pro Ser 325 330 335 Leu Ser Ser Gln Ala Leu Pro Ser Pro Arg Leu ProThr Thr Asp Gly 340 345 350 Ala His Pro Gln Pro Ile Ser Pro Ile Pro GlyGly Val Ser Ser Ser 355 360 365 Gly Leu Ser Arg Met Gly Ala Val Pro ValMet Val Pro Ala Gln Ser 370 375 380 Gln Ala Gly Ser Leu Val 385 390 4022 DNA Artificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 40 agggtctcca ggagaaagac tc 22 41 24 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 41 attgtgggcc ttgcagacat agac 24 42 50 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 42 ggccacagca tcaaaacctt agaactcaat gtactggttcctccagctcc 50 43 18 DNA Artificial Sequence Description of ArtificialSequence Synthetic oligonucleotide probe 43 gtgtgacaca gcgtgggc 18 44 18DNA Artificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 44 gaccggcagg cttctgcg 18 45 25 DNA ArtificialSequence Description of Artificial Sequence Synthetic oligonucleotideprobe 45 cagcagcttc agccaccagg agtgg 25 46 24 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe 46ctgagccgtg ggctgcagtc tcgc 24 47 45 DNA Artificial Sequence Descriptionof Artificial Sequence Synthetic oligonucleotide probe 47 ccgactacgactggttcttc atcatgcagg atgacacata tgtgc 45 48 2822 DNA Homo sapiens 48cgccaccact gcggccaccg ccaatgaaac gcctcccgct cctagtggtt ttttccactt 60tgttgaattg ttcctatact caaaattgca ccaagacacc ttgtctccca aatgcaaaat 120gtgaaatacg caatggaatt gaagcctgct attgcaacat gggattttca ggaaatggtg 180tcacaatttg tgaagatgat aatgaatgtg gaaatttaac tcagtcctgt ggcgaaaatg 240ctaattgcac taacacagaa ggaagttatt attgtatgtg tgtacctggc ttcagatcca 300gcagtaacca agacaggttt atcactaatg atggaaccgt ctgtatagaa aatgtgaatg 360caaactgcca tttagataat gtctgtatag ctgcaaatat taataaaact ttaacaaaaa 420tcagatccat aaaagaacct gtggctttgc tacaagaagt ctatagaaat tctgtgacag 480atctttcacc aacagatata attacatata tagaaatatt agctgaatca tcttcattac 540taggttacaa gaacaacact atctcagcca aggacaccct ttctaactca actcttactg 600aatttgtaaa aaccgtgaat aattttgttc aaagggatac atttgtagtt tgggacaagt 660tatctgtgaa tcataggaga acacatctta caaaactcat gcacactgtt gaacaagcta 720ctttaaggat atcccagagc ttccaaaaga ccacagagtt tgatacaaat tcaacggata 780tagctctcaa agttttcttt tttgattcat ataacatgaa acatattcat cctcatatga 840atatggatgg agactacata aatatatttc caaagagaaa agctgcatat gattcaaatg 900gcaatgttgc agttgcattt ttatattata agagtattgg tcctttgctt tcatcatctg 960acaacttctt attgaaacct caaaattatg ataattctga agaggaggaa agagtcatat 1020cttcagtaat ttcagtctca atgagctcaa acccacccac attatatgaa cttgaaaaaa 1080taacatttac attaagtcat cgaaaggtca cagataggta taggagtcta tgtgcatttt 1140ggaattactc acctgatacc atgaatggca gctggtcttc agagggctgt gagctgacat 1200actcaaatga gacccacacc tcatgccgct gtaatcacct gacacatttt gcaattttga 1260tgtcctctgg tccttccatt ggtattaaag attataatat tcttacaagg atcactcaac 1320taggaataat tatttcactg atttgtcttg ccatatgcat ttttaccttc tggttcttca 1380gtgaaattca aagcaccagg acaacaattc acaaaaatct ttgctgtagc ctatttcttg 1440ctgaacttgt ttttcttgtt gggatcaata caaatactaa taagctcttc tgttcaatca 1500ttgccggact gctacactac ttctttttag ctgcttttgc atggatgtgc attgaaggca 1560tacatctcta tctcattgtt gtgggtgtca tctacaacaa gggatttttg cacaagaatt 1620tttatatctt tggctatcta agcccagccg tggtagttgg attttcggca gcactaggat 1680acagatatta tggcacaacc aaagtatgtt ggcttagcac cgaaaacaac tttatttgga 1740gttttatagg accagcatgc ctaatcattc ttgttaatct cttggctttt ggagtcatca 1800tatacaaagt ttttcgtcac actgcagggt tgaaaccaga agttagttgc tttgagaaca 1860taaggtcttg tgcaagagga gccctcgctc ttctgttcct tctcggcacc acctggatct 1920ttggggttct ccatgttgtg cacgcatcag tggttacagc ttacctcttc acagtcagca 1980atgctttcca ggggatgttc atttttttat tcctgtgtgt tttatctaga aagattcaag 2040aagaatatta cagattgttc aaaaatgtcc cctgttgttt tggatgttta aggtaaacat 2100agagaatggt ggataattac aactgcacaa aaataaaaat tccaagctgt ggatgaccaa 2160tgtataaaaa tgactcatca aattatccaa ttattaacta ctagacaaaa agtattttaa 2220atcagttttt ctgtttatgc tataggaact gtagataata aggtaaaatt atgtatcata 2280tagatatact atgtttttct atgtgaaata gttctgtcaa aaatagtatt gcagatattt 2340ggaaagtaat tggtttctca ggagtgatat cactgcaccc aaggaaagat tttctttcta 2400acacgagaag tatatgaatg tcctgaagga aaccactggc ttgatatttc tgtgactcgt 2460gttgcctttg aaactagtcc cctaccacct cggtaatgag ctccattaca gaaagtggaa 2520cataagagaa tgaaggggca gaatatcaaa cagtgaaaag ggaatgataa gatgtatttt 2580gaatgaactg ttttttctgt agactagctg agaaattgtt gacataaaat aaagaattga 2640agaaacacat tttaccattt tgtgaattgt tctgaactta aatgtccact aaaacaactt 2700agacttctgt ttgctaaatc tgtttctttt tctaatattc taaaaaaaaa aaaaaggttt 2760acctccacaa attgaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 2820aa 2822 49 690 PRT Homo sapiens 49 Met Lys Arg Leu Pro Leu Leu Val ValPhe Ser Thr Leu Leu Asn Cys 1 5 10 15 Ser Tyr Thr Gln Asn Cys Thr LysThr Pro Cys Leu Pro Asn Ala Lys 20 25 30 Cys Glu Ile Arg Asn Gly Ile GluAla Cys Tyr Cys Asn Met Gly Phe 35 40 45 Ser Gly Asn Gly Val Thr Ile CysGlu Asp Asp Asn Glu Cys Gly Asn 50 55 60 Leu Thr Gln Ser Cys Gly Glu AsnAla Asn Cys Thr Asn Thr Glu Gly 65 70 75 80 Ser Tyr Tyr Cys Met Cys ValPro Gly Phe Arg Ser Ser Ser Asn Gln 85 90 95 Asp Arg Phe Ile Thr Asn AspGly Thr Val Cys Ile Glu Asn Val Asn 100 105 110 Ala Asn Cys His Leu AspAsn Val Cys Ile Ala Ala Asn Ile Asn Lys 115 120 125 Thr Leu Thr Lys IleArg Ser Ile Lys Glu Pro Val Ala Leu Leu Gln 130 135 140 Glu Val Tyr ArgAsn Ser Val Thr Asp Leu Ser Pro Thr Asp Ile Ile 145 150 155 160 Thr TyrIle Glu Ile Leu Ala Glu Ser Ser Ser Leu Leu Gly Tyr Lys 165 170 175 AsnAsn Thr Ile Ser Ala Lys Asp Thr Leu Ser Asn Ser Thr Leu Thr 180 185 190Glu Phe Val Lys Thr Val Asn Asn Phe Val Gln Arg Asp Thr Phe Val 195 200205 Val Trp Asp Lys Leu Ser Val Asn His Arg Arg Thr His Leu Thr Lys 210215 220 Leu Met His Thr Val Glu Gln Ala Thr Leu Arg Ile Ser Gln Ser Phe225 230 235 240 Gln Lys Thr Thr Glu Phe Asp Thr Asn Ser Thr Asp Ile AlaLeu Lys 245 250 255 Val Phe Phe Phe Asp Ser Tyr Asn Met Lys His Ile HisPro His Met 260 265 270 Asn Met Asp Gly Asp Tyr Ile Asn Ile Phe Pro LysArg Lys Ala Ala 275 280 285 Tyr Asp Ser Asn Gly Asn Val Ala Val Ala PheLeu Tyr Tyr Lys Ser 290 295 300 Ile Gly Pro Leu Leu Ser Ser Ser Asp AsnPhe Leu Leu Lys Pro Gln 305 310 315 320 Asn Tyr Asp Asn Ser Glu Glu GluGlu Arg Val Ile Ser Ser Val Ile 325 330 335 Ser Val Ser Met Ser Ser AsnPro Pro Thr Leu Tyr Glu Leu Glu Lys 340 345 350 Ile Thr Phe Thr Leu SerHis Arg Lys Val Thr Asp Arg Tyr Arg Ser 355 360 365 Leu Cys Ala Phe TrpAsn Tyr Ser Pro Asp Thr Met Asn Gly Ser Trp 370 375 380 Ser Ser Glu GlyCys Glu Leu Thr Tyr Ser Asn Glu Thr His Thr Ser 385 390 395 400 Cys ArgCys Asn His Leu Thr His Phe Ala Ile Leu Met Ser Ser Gly 405 410 415 ProSer Ile Gly Ile Lys Asp Tyr Asn Ile Leu Thr Arg Ile Thr Gln 420 425 430Leu Gly Ile Ile Ile Ser Leu Ile Cys Leu Ala Ile Cys Ile Phe Thr 435 440445 Phe Trp Phe Phe Ser Glu Ile Gln Ser Thr Arg Thr Thr Ile His Lys 450455 460 Asn Leu Cys Cys Ser Leu Phe Leu Ala Glu Leu Val Phe Leu Val Gly465 470 475 480 Ile Asn Thr Asn Thr Asn Lys Leu Phe Cys Ser Ile Ile AlaGly Leu 485 490 495 Leu His Tyr Phe Phe Leu Ala Ala Phe Ala Trp Met CysIle Glu Gly 500 505 510 Ile His Leu Tyr Leu Ile Val Val Gly Val Ile TyrAsn Lys Gly Phe 515 520 525 Leu His Lys Asn Phe Tyr Ile Phe Gly Tyr LeuSer Pro Ala Val Val 530 535 540 Val Gly Phe Ser Ala Ala Leu Gly Tyr ArgTyr Tyr Gly Thr Thr Lys 545 550 555 560 Val Cys Trp Leu Ser Thr Glu AsnAsn Phe Ile Trp Ser Phe Ile Gly 565 570 575 Pro Ala Cys Leu Ile Ile LeuVal Asn Leu Leu Ala Phe Gly Val Ile 580 585 590 Ile Tyr Lys Val Phe ArgHis Thr Ala Gly Leu Lys Pro Glu Val Ser 595 600 605 Cys Phe Glu Asn IleArg Ser Cys Ala Arg Gly Ala Leu Ala Leu Leu 610 615 620 Phe Leu Leu GlyThr Thr Trp Ile Phe Gly Val Leu His Val Val His 625 630 635 640 Ala SerVal Val Thr Ala Tyr Leu Phe Thr Val Ser Asn Ala Phe Gln 645 650 655 GlyMet Phe Ile Phe Leu Phe Leu Cys Val Leu Ser Arg Lys Ile Gln 660 665 670Glu Glu Tyr Tyr Arg Leu Phe Lys Asn Val Pro Cys Cys Phe Gly Cys 675 680685 Leu Arg 690 50 589 DNA Homo sapiens modified_base (61) a, t, c or g50 tggaaacata tcctccctca tatgaatatg gatggagact acataaatat atttccaaag 60ngaaaagccg gcatatggat tcaaatggca atgttgcagt tgcattttta tattataaga 120gtattggtcc ctttgctttc atcatctgac aacttcttat tgaaacctca aaattatgat 180aattctgaag aggaggaaag agtcatatct tcagtaattt cagtctcaat gagctcaaac 240ccacccacat tatatgaact tgaaaaaata acatttacat taagtcatcg aaaggtcaca 300gataggtata ggagtctatg tggcattttg gaatactcac ctgataccat gaatggcagc 360tggtcttcag agggctgtga gctgacatac tcaaatgaga cccacacctc atgccgctgt 420aatcacctga cacattttgc aattttgatg tcctctggtc cttccattgg tattaaagat 480tataatattc ttacaaggat cactcaacta ggaataatta tttcactgat ttgtcttgcc 540atatgcattt ttaccttctg gttcttcagt gaaattcaaa gcaccagga 589 51 20 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 51 ggtaatgagc tccattacag 20 52 18 DNA ArtificialSequence Description of Artificial Sequence Synthetic oligonucleotideprobe 52 ggagtagaaa gcgcatgg 18 53 22 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe 53cacctgatac catgaatggc ag 22 54 18 DNA Artificial Sequence Description ofArtificial Sequence Synthetic oligonucleotide probe 54 cgagctcgaattaattcg 18 55 18 DNA Artificial Sequence Description of ArtificialSequence Synthetic oligonucleotide probe 55 ggatctcctg agctcagg 18 56 23DNA Artificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 56 cctagttgag tgatccttgt aag 23 57 50 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 57 atgagaccca cacctcatgc cgctgtaatc acctgacacattttgcaatt 50 58 2137 DNA Homo sapiens 58 gctcccagcc aagaacctcggggccgctgc gcggtgggga ggagttcccc gaaacccggc 60 cgctaagcga ggcctcctcctcccgcagat ccgaacggcc tgggcggggt caccccggct 120 gggacaagaa gccgccgcctgcctgcccgg gcccggggag ggggctgggg ctggggccgg 180 aggcggggtg tgagtgggtgtgtgcggggg gcggaggctt gatgcaatcc cgataagaaa 240 tgctcgggtg tcttgggcacctacccgtgg ggcccgtaag gcgctactat ataaggctgc 300 cggcccggag ccgccgcgccgtcagagcag gagcgctgcg tccaggatct agggccacga 360 ccatcccaac ccggcactcacagccccgca gcgcatcccg gtcgccgccc agcctcccgc 420 acccccatcg ccggagctgcgccgagagcc ccagggaggt gccatgcgga gcgggtgtgt 480 ggtggtccac gtatggatcctggccggcct ctggctggcc gtggccgggc gccccctcgc 540 cttctcggac gcggggccccacgtgcacta cggctggggc gaccccatcc gcctgcggca 600 cctgtacacc tccggcccccacgggctctc cagctgcttc ctgcgcatcc gtgccgacgg 660 cgtcgtggac tgcgcgcggggccagagcgc gcacagtttg ctggagatca aggcagtcgc 720 tctgcggacc gtggccatcaagggcgtgca cagcgtgcgg tacctctgca tgggcgccga 780 cggcaagatg caggggctgcttcagtactc ggaggaagac tgtgctttcg aggaggagat 840 ccgcccagat ggctacaatgtgtaccgatc cgagaagcac cgcctcccgg tctccctgag 900 cagtgccaaa cagcggcagctgtacaagaa cagaggcttt cttccactct ctcatttcct 960 gcccatgctg cccatggtcccagaggagcc tgaggacctc aggggccact tggaatctga 1020 catgttctct tcgcccctggagaccgacag catggaccca tttgggcttg tcaccggact 1080 ggaggccgtg aggagtcccagctttgagaa gtaactgaga ccatgcccgg gcctcttcac 1140 tgctgccagg ggctgtggtacctgcagcgt gggggacgtg cttctacaag aacagtcctg 1200 agtccacgtt ctgtttagctttaggaagaa acatctagaa gttgtacata ttcagagttt 1260 tccattggca gtgccagtttctagccaata gacttgtctg atcataacat tgtaagcctg 1320 tagcttgccc agctgctgcctgggccccca ttctgctccc tcgaggttgc tggacaagct 1380 gctgcactgt ctcagttctgcttgaatacc tccatcgatg gggaactcac ttcctttgga 1440 aaaattctta tgtcaagctgaaattctcta attttttctc atcacttccc caggagcagc 1500 cagaagacag gcagtagttttaatttcagg aacaggtgat ccactctgta aaacagcagg 1560 taaatttcac tcaaccccatgtgggaattg atctatatct ctacttccag ggaccatttg 1620 cccttcccaa atccctccaggccagaactg actggagcag gcatggccca ccaggcttca 1680 ggagtagggg aagcctggagccccactcca gccctgggac aacttgagaa ttccccctga 1740 ggccagttct gtcatggatgctgtcctgag aataacttgc tgtcccggtg tcacctgctt 1800 ccatctccca gcccaccagccctctgccca cctcacatgc ctccccatgg attggggcct 1860 cccaggcccc ccaccttatgtcaacctgca cttcttgttc aaaaatcagg aaaagaaaag 1920 atttgaagac cccaagtcttgtcaataact tgctgtgtgg aagcagcggg ggaagaccta 1980 gaaccctttc cccagcacttggttttccaa catgatattt atgagtaatt tattttgata 2040 tgtacatctc ttattttcttacattattta tgcccccaaa ttatatttat gtatgtaagt 2100 gaggtttgtt ttgtatattaaaatggagtt tgtttgt 2137 59 216 PRT Homo sapiens 59 Met Arg Ser Gly CysVal Val Val His Val Trp Ile Leu Ala Gly Leu 1 5 10 15 Trp Leu Ala ValAla Gly Arg Pro Leu Ala Phe Ser Asp Ala Gly Pro 20 25 30 His Val His TyrGly Trp Gly Asp Pro Ile Arg Leu Arg His Leu Tyr 35 40 45 Thr Ser Gly ProHis Gly Leu Ser Ser Cys Phe Leu Arg Ile Arg Ala 50 55 60 Asp Gly Val ValAsp Cys Ala Arg Gly Gln Ser Ala His Ser Leu Leu 65 70 75 80 Glu Ile LysAla Val Ala Leu Arg Thr Val Ala Ile Lys Gly Val His 85 90 95 Ser Val ArgTyr Leu Cys Met Gly Ala Asp Gly Lys Met Gln Gly Leu 100 105 110 Leu GlnTyr Ser Glu Glu Asp Cys Ala Phe Glu Glu Glu Ile Arg Pro 115 120 125 AspGly Tyr Asn Val Tyr Arg Ser Glu Lys His Arg Leu Pro Val Ser 130 135 140Leu Ser Ser Ala Lys Gln Arg Gln Leu Tyr Lys Asn Arg Gly Phe Leu 145 150155 160 Pro Leu Ser His Phe Leu Pro Met Leu Pro Met Val Pro Glu Glu Pro165 170 175 Glu Asp Leu Arg Gly His Leu Glu Ser Asp Met Phe Ser Ser ProLeu 180 185 190 Glu Thr Asp Ser Met Asp Pro Phe Gly Leu Val Thr Gly LeuGlu Ala 195 200 205 Val Arg Ser Pro Ser Phe Glu Lys 210 215 60 26 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 60 atccgcccag atggctacaa tgtgta 26 61 42 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 61 gcctcccggt ctccctgagc agtgccaaac agcggcagtg ta42 62 22 DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 62 ccagtccggt gacaagccca aa 22 63 1295DNA Homo sapiens 63 cccagaagtt caagggcccc cggcctcctg cgctcctgccgccgggaccc tcgacctcct 60 cagagcagcc ggctgccgcc ccgggaagat ggcgaggaggagccgccacc gcctcctcct 120 gctgctgctg cgctacctgg tggtcgccct gggctatcataaggcctatg ggttttctgc 180 cccaaaagac caacaagtag tcacagcagt agagtaccaagaggctattt tagcctgcaa 240 aaccccaaag aagactgttt cctccagatt agagtggaagaaactgggtc ggagtgtctc 300 ctttgtctac tatcaacaga ctcttcaagg tgattttaaaaatcgagctg agatgataga 360 tttcaatatc cggatcaaaa atgtgacaag aagtgatgcggggaaatatc gttgtgaagt 420 tagtgcccca tctgagcaag gccaaaacct ggaagaggatacagtcactc tggaagtatt 480 agtggctcca gcagttccat catgtgaagt accctcttctgctctgagtg gaactgtggt 540 agagctacga tgtcaagaca aagaagggaa tccagctcctgaatacacat ggtttaagga 600 tggcatccgt ttgctagaaa atcccagact tggctcccaaagcaccaaca gctcatacac 660 aatgaataca aaaactggaa ctctgcaatt taatactgtttccaaactgg acactggaga 720 atattcctgt gaagcccgca attctgttgg atatcgcaggtgtcctggga aacgaatgca 780 agtagatgat ctcaacataa gtggcatcat agcagccgtagtagttgtgg ccttagtgat 840 ttccgtttgt ggccttggtg tatgctatgc tcagaggaaaggctactttt caaaagaaac 900 ctccttccag aagagtaatt cttcatctaa agccacgacaatgagtgaaa atgtgcagtg 960 gctcacgcct gtaatcccag cactttggaa ggccgcggcgggcggatcac gaggtcagga 1020 gttctagacc agtctggcca atatggtgaa accccatctctactaaaata caaaaattag 1080 ctgggcatgg tggcatgtgc ctgcagttcc agctgcttgggagacaggag aatcacttga 1140 acccgggagg cggaggttgc agtgagctga gatcacgccactgcagtcca gcctgggtaa 1200 cagagcaaga ttccatctca aaaaataaaa taaataaataaataaatact ggtttttacc 1260 tgtagaattc ttacaataaa tatagcttga tattc 129564 312 PRT Homo sapiens 64 Met Ala Arg Arg Ser Arg His Arg Leu Leu LeuLeu Leu Leu Arg Tyr 1 5 10 15 Leu Val Val Ala Leu Gly Tyr His Lys AlaTyr Gly Phe Ser Ala Pro 20 25 30 Lys Asp Gln Gln Val Val Thr Ala Val GluTyr Gln Glu Ala Ile Leu 35 40 45 Ala Cys Lys Thr Pro Lys Lys Thr Val SerSer Arg Leu Glu Trp Lys 50 55 60 Lys Leu Gly Arg Ser Val Ser Phe Val TyrTyr Gln Gln Thr Leu Gln 65 70 75 80 Gly Asp Phe Lys Asn Arg Ala Glu MetIle Asp Phe Asn Ile Arg Ile 85 90 95 Lys Asn Val Thr Arg Ser Asp Ala GlyLys Tyr Arg Cys Glu Val Ser 100 105 110 Ala Pro Ser Glu Gln Gly Gln AsnLeu Glu Glu Asp Thr Val Thr Leu 115 120 125 Glu Val Leu Val Ala Pro AlaVal Pro Ser Cys Glu Val Pro Ser Ser 130 135 140 Ala Leu Ser Gly Thr ValVal Glu Leu Arg Cys Gln Asp Lys Glu Gly 145 150 155 160 Asn Pro Ala ProGlu Tyr Thr Trp Phe Lys Asp Gly Ile Arg Leu Leu 165 170 175 Glu Asn ProArg Leu Gly Ser Gln Ser Thr Asn Ser Ser Tyr Thr Met 180 185 190 Asn ThrLys Thr Gly Thr Leu Gln Phe Asn Thr Val Ser Lys Leu Asp 195 200 205 ThrGly Glu Tyr Ser Cys Glu Ala Arg Asn Ser Val Gly Tyr Arg Arg 210 215 220Cys Pro Gly Lys Arg Met Gln Val Asp Asp Leu Asn Ile Ser Gly Ile 225 230235 240 Ile Ala Ala Val Val Val Val Ala Leu Val Ile Ser Val Cys Gly Leu245 250 255 Gly Val Cys Tyr Ala Gln Arg Lys Gly Tyr Phe Ser Lys Glu ThrSer 260 265 270 Phe Gln Lys Ser Asn Ser Ser Ser Lys Ala Thr Thr Met SerGlu Asn 275 280 285 Val Gln Trp Leu Thr Pro Val Ile Pro Ala Leu Trp LysAla Ala Ala 290 295 300 Gly Gly Ser Arg Gly Gln Glu Phe 305 310 65 22DNA Artificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 65 atcgttgtga agttagtgcc cc 22 66 23 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 66 acctgcgata tccaacagaa ttg 23 67 48 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 67 ggaagaggat acagtcactc tggaagtatt agtggctccagcagttcc 48 68 2639 DNA Homo sapiens 68 gacatcggag gtgggctagc actgaaactgcttttcaaga cgaggaagag gaggagaaag 60 agaaagaaga ggaagatgtt gggcaacatttatttaacat gctccacagc ccggaccctg 120 gcatcatgct gctattcctg caaatactgaagaagcatgg gatttaaata ttttacttct 180 aaataaatga attactcaat ctcctatgaccatctataca tactccacct tcaaaaagta 240 catcaatatt atatcattaa ggaaatagtaaccttctctt ctccaatatg catgacattt 300 ttggacaatg caattgtggc actggcacttatttcagtga agaaaaactt tgtggttcta 360 tggcattcat catttgacaa atgcaagcatcttccttatc aatcagctcc tattgaactt 420 actagcactg actgtggaat ccttaagggcccattacatt tctgaagaag aaagctaaga 480 tgaaggacat gccactccga attcatgtgctacttggcct agctatcact acactagtac 540 aagctgtaga taaaaaagtg gattgtccacggttatgtac gtgtgaaatc aggccttggt 600 ttacacccag atccatttat atggaagcatctacagtgga ttgtaatgat ttaggtcttt 660 taactttccc agccagattg ccagctaacacacagattct tctcctacag actaacaata 720 ttgcaaaaat tgaatactcc acagactttccagtaaacct tactggcctg gatttatctc 780 aaaacaattt atcttcagtc accaatattaatgtaaaaaa gatgcctcag ctcctttctg 840 tgtacctaga ggaaaacaaa cttactgaactgcctgaaaa atgtctgtcc gaactgagca 900 acttacaaga actctatatt aatcacaacttgctttctac aatttcacct ggagccttta 960 ttggcctaca taatcttctt cgacttcatctcaattcaaa tagattgcag atgatcaaca 1020 gtaagtggtt tgatgctctt ccaaatctagagattctgat gattggggaa aatccaatta 1080 tcagaatcaa agacatgaac tttaagcctcttatcaatct tcgcagcctg gttatagctg 1140 gtataaacct cacagaaata ccagataacgccttggttgg actggaaaac ttagaaagca 1200 tctcttttta cgataacagg cttattaaagtaccccatgt tgctcttcaa aaagttgtaa 1260 atctcaaatt tttggatcta aataaaaatcctattaatag aatacgaagg ggtgatttta 1320 gcaatatgct acacttaaaa gagttggggataaataatat gcctgagctg atttccatcg 1380 atagtcttgc tgtggataac ctgccagatttaagaaaaat agaagctact aacaacccta 1440 gattgtctta cattcacccc aatgcatttttcagactccc caagctggaa tcactcatgc 1500 tgaacagcaa tgctctcagt gccctgtaccatggtaccat tgagtctctg ccaaacctca 1560 aggaaatcag catacacagt aaccccatcaggtgtgactg tgtcatccgt tggatgaaca 1620 tgaacaaaac caacattcga ttcatggagccagattcact gttttgcgtg gacccacctg 1680 aattccaagg tcagaatgtt cggcaagtgcatttcaggga catgatggaa atttgtctcc 1740 ctcttatagc tcctgagagc tttccttctaatctaaatgt agaagctggg agctatgttt 1800 cctttcactg tagagctact gcagaaccacagcctgaaat ctactggata acaccttctg 1860 gtcaaaaact cttgcctaat accctgacagacaagttcta tgtccattct gagggaacac 1920 tagatataaa tggcgtaact cccaaagaagggggtttata tacttgtata gcaactaacc 1980 tagttggcgc tgacttgaag tctgttatgatcaaagtgga tggatctttt ccacaagata 2040 acaatggctc tttgaatatt aaaataagagatattcaggc caattcagtt ttggtgtcct 2100 ggaaagcaag ttctaaaatt ctcaaatctagtgttaaatg gacagccttt gtcaagactg 2160 aaaattctca tgctgcgcaa agtgctcgaataccatctga tgtcaaggta tataatctta 2220 ctcatctgaa tccatcaact gagtataaaatttgtattga tattcccacc atctatcaga 2280 aaaacagaaa aaaatgtgta aatgtcaccaccaaaggttt gcaccctgat caaaaagagt 2340 atgaaaagaa taataccaca acacttatggcctgtcttgg aggccttctg gggattattg 2400 gtgtgatatg tcttatcagc tgcctctctccagaaatgaa ctgtgatggt ggacacagct 2460 atgtgaggaa ttacttacag aaaccaacctttgcattagg tgagctttat cctcctctga 2520 taaatctctg ggaagcagga aaagaaaaaagtacatcact gaaagtaaaa gcaactgtta 2580 taggtttacc aacaaatatg tcctaaaaaccaccaaggaa acctactcca aaaatgaac 2639 69 708 PRT Homo sapiens 69 Met LysAsp Met Pro Leu Arg Ile His Val Leu Leu Gly Leu Ala Ile 1 5 10 15 ThrThr Leu Val Gln Ala Val Asp Lys Lys Val Asp Cys Pro Arg Leu 20 25 30 CysThr Cys Glu Ile Arg Pro Trp Phe Thr Pro Arg Ser Ile Tyr Met 35 40 45 GluAla Ser Thr Val Asp Cys Asn Asp Leu Gly Leu Leu Thr Phe Pro 50 55 60 AlaArg Leu Pro Ala Asn Thr Gln Ile Leu Leu Leu Gln Thr Asn Asn 65 70 75 80Ile Ala Lys Ile Glu Tyr Ser Thr Asp Phe Pro Val Asn Leu Thr Gly 85 90 95Leu Asp Leu Ser Gln Asn Asn Leu Ser Ser Val Thr Asn Ile Asn Val 100 105110 Lys Lys Met Pro Gln Leu Leu Ser Val Tyr Leu Glu Glu Asn Lys Leu 115120 125 Thr Glu Leu Pro Glu Lys Cys Leu Ser Glu Leu Ser Asn Leu Gln Glu130 135 140 Leu Tyr Ile Asn His Asn Leu Leu Ser Thr Ile Ser Pro Gly AlaPhe 145 150 155 160 Ile Gly Leu His Asn Leu Leu Arg Leu His Leu Asn SerAsn Arg Leu 165 170 175 Gln Met Ile Asn Ser Lys Trp Phe Asp Ala Leu ProAsn Leu Glu Ile 180 185 190 Leu Met Ile Gly Glu Asn Pro Ile Ile Arg IleLys Asp Met Asn Phe 195 200 205 Lys Pro Leu Ile Asn Leu Arg Ser Leu ValIle Ala Gly Ile Asn Leu 210 215 220 Thr Glu Ile Pro Asp Asn Ala Leu ValGly Leu Glu Asn Leu Glu Ser 225 230 235 240 Ile Ser Phe Tyr Asp Asn ArgLeu Ile Lys Val Pro His Val Ala Leu 245 250 255 Gln Lys Val Val Asn LeuLys Phe Leu Asp Leu Asn Lys Asn Pro Ile 260 265 270 Asn Arg Ile Arg ArgGly Asp Phe Ser Asn Met Leu His Leu Lys Glu 275 280 285 Leu Gly Ile AsnAsn Met Pro Glu Leu Ile Ser Ile Asp Ser Leu Ala 290 295 300 Val Asp AsnLeu Pro Asp Leu Arg Lys Ile Glu Ala Thr Asn Asn Pro 305 310 315 320 ArgLeu Ser Tyr Ile His Pro Asn Ala Phe Phe Arg Leu Pro Lys Leu 325 330 335Glu Ser Leu Met Leu Asn Ser Asn Ala Leu Ser Ala Leu Tyr His Gly 340 345350 Thr Ile Glu Ser Leu Pro Asn Leu Lys Glu Ile Ser Ile His Ser Asn 355360 365 Pro Ile Arg Cys Asp Cys Val Ile Arg Trp Met Asn Met Asn Lys Thr370 375 380 Asn Ile Arg Phe Met Glu Pro Asp Ser Leu Phe Cys Val Asp ProPro 385 390 395 400 Glu Phe Gln Gly Gln Asn Val Arg Gln Val His Phe ArgAsp Met Met 405 410 415 Glu Ile Cys Leu Pro Leu Ile Ala Pro Glu Ser PhePro Ser Asn Leu 420 425 430 Asn Val Glu Ala Gly Ser Tyr Val Ser Phe HisCys Arg Ala Thr Ala 435 440 445 Glu Pro Gln Pro Glu Ile Tyr Trp Ile ThrPro Ser Gly Gln Lys Leu 450 455 460 Leu Pro Asn Thr Leu Thr Asp Lys PheTyr Val His Ser Glu Gly Thr 465 470 475 480 Leu Asp Ile Asn Gly Val ThrPro Lys Glu Gly Gly Leu Tyr Thr Cys 485 490 495 Ile Ala Thr Asn Leu ValGly Ala Asp Leu Lys Ser Val Met Ile Lys 500 505 510 Val Asp Gly Ser PhePro Gln Asp Asn Asn Gly Ser Leu Asn Ile Lys 515 520 525 Ile Arg Asp IleGln Ala Asn Ser Val Leu Val Ser Trp Lys Ala Ser 530 535 540 Ser Lys IleLeu Lys Ser Ser Val Lys Trp Thr Ala Phe Val Lys Thr 545 550 555 560 GluAsn Ser His Ala Ala Gln Ser Ala Arg Ile Pro Ser Asp Val Lys 565 570 575Val Tyr Asn Leu Thr His Leu Asn Pro Ser Thr Glu Tyr Lys Ile Cys 580 585590 Ile Asp Ile Pro Thr Ile Tyr Gln Lys Asn Arg Lys Lys Cys Val Asn 595600 605 Val Thr Thr Lys Gly Leu His Pro Asp Gln Lys Glu Tyr Glu Lys Asn610 615 620 Asn Thr Thr Thr Leu Met Ala Cys Leu Gly Gly Leu Leu Gly IleIle 625 630 635 640 Gly Val Ile Cys Leu Ile Ser Cys Leu Ser Pro Glu MetAsn Cys Asp 645 650 655 Gly Gly His Ser Tyr Val Arg Asn Tyr Leu Gln LysPro Thr Phe Ala 660 665 670 Leu Gly Glu Leu Tyr Pro Pro Leu Ile Asn LeuTrp Glu Ala Gly Lys 675 680 685 Glu Lys Ser Thr Ser Leu Lys Val Lys AlaThr Val Ile Gly Leu Pro 690 695 700 Thr Asn Met Ser 705 70 1305 DNA Homosapiens 70 gcccgggact ggcgcaaggt gcccaagcaa ggaaagaaat aatgaagagacacatgtgtt 60 agctgcagcc ttttgaaaca cgcaagaagg aaatcaatag tgtggacagggctggaacct 120 ttaccacgct tgttggagta gatgaggaat gggctcgtga ttatgctgacattccagcat 180 gaatctggta gacctgtggt taacccgttc cctctccatg tgtctcctcctacaaagttt 240 tgttcttatg atactgtgct ttcattctgc cagtatgtgt cccaagggctgtctttgttc 300 ttcctctggg ggtttaaatg tcacctgtag caatgcaaat ctcaaggaaatacctagaga 360 tcttcctcct gaaacagtct tactgtatct ggactccaat cagatcacatctattcccaa 420 tgaaattttt aaggacctcc atcaactgag agttctcaac ctgtccaaaaatggcattga 480 gtttatcgat gagcatgcct tcaaaggagt agctgaaacc ttgcagactctggacttgtc 540 cgacaatcgg attcaaagtg tgcacaaaaa tgccttcaat aacctgaaggccagggccag 600 aattgccaac aacccctggc actgcgactg tactctacag caagttctgaggagcatggc 660 gtccaatcat gagacagccc acaacgtgat ctgtaaaacg tccgtgttggatgaacatgc 720 tggcagacca ttcctcaatg ctgccaacga cgctgacctt tgtaacctccctaaaaaaac 780 taccgattat gccatgctgg tcaccatgtt tggctggttc actatggtgatctcatatgt 840 ggtatattat gtgaggcaaa atcaggagga tgcccggaga cacctcgaatacttgaaatc 900 cctgccaagc aggcagaaga aagcagatga acctgatgat attagcactgtggtatagtg 960 tccaaactga ctgtcattga gaaagaaaga aagtagtttg cgattgcagtagaaataagt 1020 ggtttacttc tcccatccat tgtaaacatt tgaaactttg tatttcagttttttttgaat 1080 tatgccactg ctgaactttt aacaaacact acaacataaa taatttgagtttaggtgatc 1140 caccccttaa ttgtaccccc gatggtatat ttctgagtaa gctactatctgaacattagt 1200 tagatccatc tcactattta ataatgaaat ttattttttt aatttaaaagcaaataaaag 1260 cttaactttg aaccatggga aaaaaaaaaa aaaaaaaaaa aaaca 130571 259 PRT Homo sapiens 71 Met Asn Leu Val Asp Leu Trp Leu Thr Arg SerLeu Ser Met Cys Leu 1 5 10 15 Leu Leu Gln Ser Phe Val Leu Met Ile LeuCys Phe His Ser Ala Ser 20 25 30 Met Cys Pro Lys Gly Cys Leu Cys Ser SerSer Gly Gly Leu Asn Val 35 40 45 Thr Cys Ser Asn Ala Asn Leu Lys Glu IlePro Arg Asp Leu Pro Pro 50 55 60 Glu Thr Val Leu Leu Tyr Leu Asp Ser AsnGln Ile Thr Ser Ile Pro 65 70 75 80 Asn Glu Ile Phe Lys Asp Leu His GlnLeu Arg Val Leu Asn Leu Ser 85 90 95 Lys Asn Gly Ile Glu Phe Ile Asp GluHis Ala Phe Lys Gly Val Ala 100 105 110 Glu Thr Leu Gln Thr Leu Asp LeuSer Asp Asn Arg Ile Gln Ser Val 115 120 125 His Lys Asn Ala Phe Asn AsnLeu Lys Ala Arg Ala Arg Ile Ala Asn 130 135 140 Asn Pro Trp His Cys AspCys Thr Leu Gln Gln Val Leu Arg Ser Met 145 150 155 160 Ala Ser Asn HisGlu Thr Ala His Asn Val Ile Cys Lys Thr Ser Val 165 170 175 Leu Asp GluHis Ala Gly Arg Pro Phe Leu Asn Ala Ala Asn Asp Ala 180 185 190 Asp LeuCys Asn Leu Pro Lys Lys Thr Thr Asp Tyr Ala Met Leu Val 195 200 205 ThrMet Phe Gly Trp Phe Thr Met Val Ile Ser Tyr Val Val Tyr Tyr 210 215 220Val Arg Gln Asn Gln Glu Asp Ala Arg Arg His Leu Glu Tyr Leu Lys 225 230235 240 Ser Leu Pro Ser Arg Gln Lys Lys Ala Asp Glu Pro Asp Asp Ile Ser245 250 255 Thr Val Val 72 2290 DNA Homo sapiens 72 accgagccgagcggaccgaa ggcgcgcccg agatgcaggt gagcaagagg atgctggcgg 60 ggggcgtgaggagcatgccc agccccctcc tggcctgctg gcagcccatc ctcctgctgg 120 tgctgggctcagtgctgtca ggctcggcca cgggctgccc gccccgctgc gagtgctccg 180 cccaggaccgcgctgtgctg tgccaccgca agtgctttgt ggcagtcccc gagggcatcc 240 ccaccgagacgcgcctgctg gacctaggca agaaccgcat caaaacgctc aaccaggacg 300 agttcgccagcttcccgcac ctggaggagc tggagctcaa cgagaacatc gtgagcgccg 360 tggagcccggcgccttcaac aacctcttca acctccggac gctgggtctc cgcagcaacc 420 gcctgaagctcatcccgcta ggcgtcttca ctggcctcag caacctgacc aagcaggaca 480 tcagcgagaacaagatcgtt atcctactgg actacatgtt tcaggacctg tacaacctca 540 agtcactggaggttggcgac aatgacctcg tctacatctc tcaccgcgcc ttcagcggcc 600 tcaacagcctggagcagctg acgctggaga aatgcaacct gacctccatc cccaccgagg 660 cgctgtcccacctgcacggc ctcatcgtcc tgaggctccg gcacctcaac atcaatgcca 720 tccgggactactccttcaag aggctgtacc gactcaaggt cttggagatc tcccactggc 780 cctacttggacaccatgaca cccaactgcc tctacggcct caacctgacg tccctgtcca 840 tcacacactgcaatctgacc gctgtgccct acctggccgt ccgccaccta gtctatctcc 900 gcttcctcaacctctcctac aaccccatca gcaccattga gggctccatg ttgcatgagc 960 tgctccggctgcaggagatc cagctggtgg gcgggcagct ggccgtggtg gagccctatg 1020 ccttccgcggcctcaactac ctgcgcgtgc tcaatgtctc tggcaaccag ctgaccacac 1080 tggaggaatcagtcttccac tcggtgggca acctggagac actcatcctg gactccaacc 1140 cgctggcctgcgactgtcgg ctcctgtggg tgttccggcg ccgctggcgg ctcaacttca 1200 accggcagcagcccacgtgc gccacgcccg agtttgtcca gggcaaggag ttcaaggact 1260 tccctgatgtgctactgccc aactacttca cctgccgccg cgcccgcatc cgggaccgca 1320 aggcccagcaggtgtttgtg gacgagggcc acacggtgca gtttgtgtgc cgggccgatg 1380 gcgacccgccgcccgccatc ctctggctct caccccgaaa gcacctggtc tcagccaaga 1440 gcaatgggcggctcacagtc ttccctgatg gcacgctgga ggtgcgctac gcccaggtac 1500 aggacaacggcacgtacctg tgcatcgcgg ccaacgcggg cggcaacgac tccatgcccg 1560 cccacctgcatgtgcgcagc tactcgcccg actggcccca tcagcccaac aagaccttcg 1620 ctttcatctccaaccagccg ggcgagggag aggccaacag cacccgcgcc actgtgcctt 1680 tccccttcgacatcaagacc ctcatcatcg ccaccaccat gggcttcatc tctttcctgg 1740 gcgtcgtcctcttctgcctg gtgctgctgt ttctctggag ccggggcaag ggcaacacaa 1800 agcacaacatcgagatcgag tatgtgcccc gaaagtcgga cgcaggcatc agctccgccg 1860 acgcgccccgcaagttcaac atgaagatga tatgaggccg gggcgggggg cagggacccc 1920 cgggcggccgggcaggggaa ggggcctggt cgccacctgc tcactctcca gtccttccca 1980 cctcctccctacccttctac acacgttctc tttctccctc ccgcctccgt cccctgctgc 2040 cccccgccagccctcaccac ctgccctcct tctaccagga cctcagaagc ccagacctgg 2100 ggaccccacctacacagggg cattgacaga ctggagttga aagccgacga accgacacgc 2160 ggcagagtcaataattcaat aaaaaagtta cgaactttct ctgtaacttg ggtttcaata 2220 attatggatttttatgaaaa cttgaaataa taaaaagaga aaaaaactaa aaaaaaaaaa 2280 aaaaaaaaaa2290 73 620 PRT Homo sapiens 73 Met Gln Val Ser Lys Arg Met Leu Ala GlyGly Val Arg Ser Met Pro 1 5 10 15 Ser Pro Leu Leu Ala Cys Trp Gln ProIle Leu Leu Leu Val Leu Gly 20 25 30 Ser Val Leu Ser Gly Ser Ala Thr GlyCys Pro Pro Arg Cys Glu Cys 35 40 45 Ser Ala Gln Asp Arg Ala Val Leu CysHis Arg Lys Cys Phe Val Ala 50 55 60 Val Pro Glu Gly Ile Pro Thr Glu ThrArg Leu Leu Asp Leu Gly Lys 65 70 75 80 Asn Arg Ile Lys Thr Leu Asn GlnAsp Glu Phe Ala Ser Phe Pro His 85 90 95 Leu Glu Glu Leu Glu Leu Asn GluAsn Ile Val Ser Ala Val Glu Pro 100 105 110 Gly Ala Phe Asn Asn Leu PheAsn Leu Arg Thr Leu Gly Leu Arg Ser 115 120 125 Asn Arg Leu Lys Leu IlePro Leu Gly Val Phe Thr Gly Leu Ser Asn 130 135 140 Leu Thr Lys Gln AspIle Ser Glu Asn Lys Ile Val Ile Leu Leu Asp 145 150 155 160 Tyr Met PheGln Asp Leu Tyr Asn Leu Lys Ser Leu Glu Val Gly Asp 165 170 175 Asn AspLeu Val Tyr Ile Ser His Arg Ala Phe Ser Gly Leu Asn Ser 180 185 190 LeuGlu Gln Leu Thr Leu Glu Lys Cys Asn Leu Thr Ser Ile Pro Thr 195 200 205Glu Ala Leu Ser His Leu His Gly Leu Ile Val Leu Arg Leu Arg His 210 215220 Leu Asn Ile Asn Ala Ile Arg Asp Tyr Ser Phe Lys Arg Leu Tyr Arg 225230 235 240 Leu Lys Val Leu Glu Ile Ser His Trp Pro Tyr Leu Asp Thr MetThr 245 250 255 Pro Asn Cys Leu Tyr Gly Leu Asn Leu Thr Ser Leu Ser IleThr His 260 265 270 Cys Asn Leu Thr Ala Val Pro Tyr Leu Ala Val Arg HisLeu Val Tyr 275 280 285 Leu Arg Phe Leu Asn Leu Ser Tyr Asn Pro Ile SerThr Ile Glu Gly 290 295 300 Ser Met Leu His Glu Leu Leu Arg Leu Gln GluIle Gln Leu Val Gly 305 310 315 320 Gly Gln Leu Ala Val Val Glu Pro TyrAla Phe Arg Gly Leu Asn Tyr 325 330 335 Leu Arg Val Leu Asn Val Ser GlyAsn Gln Leu Thr Thr Leu Glu Glu 340 345 350 Ser Val Phe His Ser Val GlyAsn Leu Glu Thr Leu Ile Leu Asp Ser 355 360 365 Asn Pro Leu Ala Cys AspCys Arg Leu Leu Trp Val Phe Arg Arg Arg 370 375 380 Trp Arg Leu Asn PheAsn Arg Gln Gln Pro Thr Cys Ala Thr Pro Glu 385 390 395 400 Phe Val GlnGly Lys Glu Phe Lys Asp Phe Pro Asp Val Leu Leu Pro 405 410 415 Asn TyrPhe Thr Cys Arg Arg Ala Arg Ile Arg Asp Arg Lys Ala Gln 420 425 430 GlnVal Phe Val Asp Glu Gly His Thr Val Gln Phe Val Cys Arg Ala 435 440 445Asp Gly Asp Pro Pro Pro Ala Ile Leu Trp Leu Ser Pro Arg Lys His 450 455460 Leu Val Ser Ala Lys Ser Asn Gly Arg Leu Thr Val Phe Pro Asp Gly 465470 475 480 Thr Leu Glu Val Arg Tyr Ala Gln Val Gln Asp Asn Gly Thr TyrLeu 485 490 495 Cys Ile Ala Ala Asn Ala Gly Gly Asn Asp Ser Met Pro AlaHis Leu 500 505 510 His Val Arg Ser Tyr Ser Pro Asp Trp Pro His Gln ProAsn Lys Thr 515 520 525 Phe Ala Phe Ile Ser Asn Gln Pro Gly Glu Gly GluAla Asn Ser Thr 530 535 540 Arg Ala Thr Val Pro Phe Pro Phe Asp Ile LysThr Leu Ile Ile Ala 545 550 555 560 Thr Thr Met Gly Phe Ile Ser Phe LeuGly Val Val Leu Phe Cys Leu 565 570 575 Val Leu Leu Phe Leu Trp Ser ArgGly Lys Gly Asn Thr Lys His Asn 580 585 590 Ile Glu Ile Glu Tyr Val ProArg Lys Ser Asp Ala Gly Ile Ser Ser 595 600 605 Ala Asp Ala Pro Arg LysPhe Asn Met Lys Met Ile 610 615 620 74 22 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe 74tcacctggag cctttattgg cc 22 75 23 DNA Artificial Sequence Description ofArtificial Sequence Synthetic oligonucleotide probe 75 ataccagctataaccaggct gcg 23 76 52 DNA Artificial Sequence Description ofArtificial Sequence Synthetic oligonucleotide probe 76 caacagtaagtggtttgatg ctcttccaaa tctagagatt ctgatgattg 50 gg 52 77 22 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 77 ccatgtgtct cctcctacaa ag 22 78 23 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 78 gggaatagat gtgatctgat tgg 23 79 50 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 79 cacctgtagc aatgcaaatc tcaaggaaat acctagagatcttcctcctg 50 80 22 DNA Artificial Sequence Description of ArtificialSequence Synthetic oligonucleotide probe 80 agcaaccgcc tgaagctcat cc 2281 24 DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 81 aaggcgcggt gaaagatgta gacg 24 82 50DNA Artificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 82 gactacatgt ttcaggacct gtacaacctc aagtcactggaggttggcga 50 83 1685 DNA Homo sapiens 83 cccacgcgtc cgcacctcggccccgggctc cgaagcggct cgggggcgcc ctttcggtca 60 acatcgtagt ccaccccctccccatcccca gcccccgggg attcaggctc gccagcgccc 120 agccagggag ccggccgggaagcgcgatgg gggccccagc cgcctcgctc ctgctcctgc 180 tcctgctgtt cgcctgctgctgggcgcccg gcggggccaa cctctcccag gacgacagcc 240 agccctggac atctgatgaaacagtggtgg ctggtggcac cgtggtgctc aagtgccaag 300 tgaaagatca cgaggactcatccctgcaat ggtctaaccc tgctcagcag actctctact 360 ttggggagaa gagagcccttcgagataatc gaattcagct ggttacctct acgccccacg 420 agctcagcat cagcatcagcaatgtggccc tggcagacga gggcgagtac acctgctcaa 480 tcttcactat gcctgtgcgaactgccaagt ccctcgtcac tgtgctagga attccacaga 540 agcccatcat cactggttataaatcttcat tacgggaaaa agacacagcc accctaaact 600 gtcagtcttc tgggagcaagcctgcagccc ggctcacctg gagaaagggt gaccaagaac 660 tccacggaga accaacccgcatacaggaag atcccaatgg taaaaccttc actgtcagca 720 gctcggtgac attccaggttacccgggagg atgatggggc gagcatcgtg tgctctgtga 780 accatgaatc tctaaagggagctgacagat ccacctctca acgcattgaa gttttataca 840 caccaactgc gatgattaggccagaccctc cccatcctcg tgagggccag aagctgttgc 900 tacactgtga gggtcgcggcaatccagtcc cccagcagta cctatgggag aaggagggca 960 gtgtgccacc cctgaagatgacccaggaga gtgccctgat cttccctttc ctcaacaaga 1020 gtgacagtgg cacctacggctgcacagcca ccagcaacat gggcagctac aaggcctact 1080 acaccctcaa tgttaatgaccccagtccgg tgccctcctc ctccagcacc taccacgcca 1140 tcatcggtgg gatcgtggctttcattgtct tcctgctgct catcatgctc atcttccttg 1200 gccactactt gatccggcacaaaggaacct acctgacaca tgaggcaaaa ggctccgacg 1260 atgctccaga cgcggacacggccatcatca atgcagaagg cgggcagtca ggaggggacg 1320 acaagaagga atatttcatctagaggcgcc tgcccacttc ctgcgccccc caggggccct 1380 gtggggactg ctggggccgtcaccaacccg gacttgtaca gagcaaccgc agggccgccc 1440 ctcccgcttg ctccccagcccacccacccc cctgtacaga atgtctgctt tgggtgcggt 1500 tttgtactcg gtttggaatggggagggagg agggcggggg gaggggaggg ttgccctcag 1560 ccctttccgt ggcttctctgcatttgggtt attattattt ttgtaacaat cccaaatcaa 1620 atctgtctcc aggctggagaggcaggagcc ctggggtgag aaaagcaaaa aacaaacaaa 1680 aaaca 1685 84 398 PRTHomo sapiens 84 Met Gly Ala Pro Ala Ala Ser Leu Leu Leu Leu Leu Leu LeuPhe Ala 1 5 10 15 Cys Cys Trp Ala Pro Gly Gly Ala Asn Leu Ser Gln AspAsp Ser Gln 20 25 30 Pro Trp Thr Ser Asp Glu Thr Val Val Ala Gly Gly ThrVal Val Leu 35 40 45 Lys Cys Gln Val Lys Asp His Glu Asp Ser Ser Leu GlnTrp Ser Asn 50 55 60 Pro Ala Gln Gln Thr Leu Tyr Phe Gly Glu Lys Arg AlaLeu Arg Asp 65 70 75 80 Asn Arg Ile Gln Leu Val Thr Ser Thr Pro His GluLeu Ser Ile Ser 85 90 95 Ile Ser Asn Val Ala Leu Ala Asp Glu Gly Glu TyrThr Cys Ser Ile 100 105 110 Phe Thr Met Pro Val Arg Thr Ala Lys Ser LeuVal Thr Val Leu Gly 115 120 125 Ile Pro Gln Lys Pro Ile Ile Thr Gly TyrLys Ser Ser Leu Arg Glu 130 135 140 Lys Asp Thr Ala Thr Leu Asn Cys GlnSer Ser Gly Ser Lys Pro Ala 145 150 155 160 Ala Arg Leu Thr Trp Arg LysGly Asp Gln Glu Leu His Gly Glu Pro 165 170 175 Thr Arg Ile Gln Glu AspPro Asn Gly Lys Thr Phe Thr Val Ser Ser 180 185 190 Ser Val Thr Phe GlnVal Thr Arg Glu Asp Asp Gly Ala Ser Ile Val 195 200 205 Cys Ser Val AsnHis Glu Ser Leu Lys Gly Ala Asp Arg Ser Thr Ser 210 215 220 Gln Arg IleGlu Val Leu Tyr Thr Pro Thr Ala Met Ile Arg Pro Asp 225 230 235 240 ProPro His Pro Arg Glu Gly Gln Lys Leu Leu Leu His Cys Glu Gly 245 250 255Arg Gly Asn Pro Val Pro Gln Gln Tyr Leu Trp Glu Lys Glu Gly Ser 260 265270 Val Pro Pro Leu Lys Met Thr Gln Glu Ser Ala Leu Ile Phe Pro Phe 275280 285 Leu Asn Lys Ser Asp Ser Gly Thr Tyr Gly Cys Thr Ala Thr Ser Asn290 295 300 Met Gly Ser Tyr Lys Ala Tyr Tyr Thr Leu Asn Val Asn Asp ProSer 305 310 315 320 Pro Val Pro Ser Ser Ser Ser Thr Tyr His Ala Ile IleGly Gly Ile 325 330 335 Val Ala Phe Ile Val Phe Leu Leu Leu Ile Met LeuIle Phe Leu Gly 340 345 350 His Tyr Leu Ile Arg His Lys Gly Thr Tyr LeuThr His Glu Ala Lys 355 360 365 Gly Ser Asp Asp Ala Pro Asp Ala Asp ThrAla Ile Ile Asn Ala Glu 370 375 380 Gly Gly Gln Ser Gly Gly Asp Asp LysLys Glu Tyr Phe Ile 385 390 395 85 22 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe 85 8622 DNA Artificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 86 87 26 DNA Artificial Sequence Description ofArtificial Sequence Synthetic oligonucleotide probe 87 88 50 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 88 89 50 DNA Artificial Sequence Description ofArtificial Sequence Synthetic oligonucleotide probe 89 90 2755 DNA Homosapiens 90 gggggttagg gaggaaggaa tccaccccca cccccccaaa cccttttcttctcctttcct 60 ggcttcggac attggagcac taaatgaact tgaattgtgt ctgtggcgagcaggatggtc 120 gctgttactt tgtgatgaga tcggggatga attgctcgct ttaaaaatgctgctttggat 180 tctgttgctg gagacgtctc tttgttttgc cgctggaaac gttacaggggacgtttgcaa 240 agagaagatc tgttcctgca atgagataga aggggaccta cacgtagactgtgaaaaaaa 300 gggcttcaca agtctgcagc gtttcactgc cccgacttcc cagttttaccatttatttct 360 gcatggcaat tccctcactc gacttttccc taatgagttc gctaacttttataatgcggt 420 tagtttgcac atggaaaaca atggcttgca tgaaatcgtt ccgggggcttttctggggct 480 gcagctggtg aaaaggctgc acatcaacaa caacaagatc aagtcttttcgaaagcagac 540 ttttctgggg ctggacgatc tggaatatct ccaggctgat tttaatttattacgagatat 600 agacccgggg gccttccagg acttgaacaa gctggaggtg ctcattttaaatgacaatct 660 catcagcacc ctacctgcca acgtgttcca gtatgtgccc atcacccacctcgacctccg 720 gggtaacagg ctgaaaacgc tgccctatga ggaggtcttg gagcaaatccctggtattgc 780 ggagatcctg ctagaggata acccttggga ctgcacctgt gatctgctctccctgaaaga 840 atggctggaa aacattccca agaatgccct gatcggccga gtggtctgcgaagcccccac 900 cagactgcag ggtaaagacc tcaatgaaac caccgaacag gacttgtgtcctttgaaaaa 960 ccgagtggat tctagtctcc cggcgccccc tgcccaagaa gagacctttgctcctggacc 1020 cctgccaact cctttcaaga caaatgggca agaggatcat gccacaccagggtctgctcc 1080 aaacggaggt acaaagatcc caggcaactg gcagatcaaa atcagacccacagcagcgat 1140 agcgacgggt agctccagga acaaaccctt agctaacagt ttaccctgccctgggggctg 1200 cagctgcgac cacatcccag ggtcgggttt aaagatgaac tgcaacaacaggaacgtgag 1260 cagcttggct gatttgaagc ccaagctctc taacgtgcag gagcttttcctacgagataa 1320 caagatccac agcatccgaa aatcgcactt tgtggattac aagaacctcattctgttgga 1380 tctgggcaac aataacatcg ctactgtaga gaacaacact ttcaagaaccttttggacct 1440 caggtggcta tacatggata gcaattacct ggacacgctg tcccgggagaaattcgcggg 1500 gctgcaaaac ctagagtacc tgaacgtgga gtacaacgct atccagctcatcctcccggg 1560 cactttcaat gccatgccca aactgaggat cctcattctc aacaacaacctgctgaggtc 1620 cctgcctgtg gacgtgttcg ctggggtctc gctctctaaa ctcagcctgcacaacaatta 1680 cttcatgtac ctcccggtgg caggggtgct ggaccagtta acctccatcatccagataga 1740 cctccacgga aacccctggg agtgctcctg cacaattgtg cctttcaagcagtgggcaga 1800 acgcttgggt tccgaagtgc tgatgagcga cctcaagtgt gagacgccggtgaacttctt 1860 tagaaaggat ttcatgctcc tctccaatga cgagatctgc cctcagctgtacgctaggat 1920 ctcgcccacg ttaacttcgc acagtaaaaa cagcactggg ttggcggagaccgggacgca 1980 ctccaactcc tacctagaca ccagcagggt gtccatctcg gtgttggtcccgggactgct 2040 gctggtgttt gtcacctccg ccttcaccgt ggtgggcatg ctcgtgtttatcctgaggaa 2100 ccgaaagcgg tccaagagac gagatgccaa ctcctccgcg tccgagattaattccctaca 2160 gacagtctgt gactcttcct actggcacaa tgggccttac aacgcagatggggcccacag 2220 agtgtatgac tgtggctctc actcgctctc agactaagac cccaaccccaataggggagg 2280 gcagagggaa ggcgatacat ccttccccac cgcaggcacc ccgggggctggaggggcgtg 2340 tacccaaatc cccgcgccat cagcctggat gggcataagt agataaataactgtgagctc 2400 gcacaaccga aagggcctga ccccttactt agctccctcc ttgaaacaaagagcagactg 2460 tggagagctg ggagagcgca gccagctcgc tctttgctga gagccccttttgacagaaag 2520 cccagcacga ccctgctgga agaactgaca gtgccctcgc cctcggccccggggcctgtg 2580 gggttggatg ccgcggttct atacatatat acatatatcc acatctatatagagagatag 2640 atatctattt ttcccctgtg gattagcccc gtgatggctc cctgttggctacgcagggat 2700 gggcagttgc acgaaggcat gaatgtattg taaataagta actttgacttctgac 2755 91 696 PRT Homo sapiens 91 Met Leu Leu Trp Ile Leu Leu LeuGlu Thr Ser Leu Cys Phe Ala Ala 1 5 10 15 Gly Asn Val Thr Gly Asp ValCys Lys Glu Lys Ile Cys Ser Cys Asn 20 25 30 Glu Ile Glu Gly Asp Leu HisVal Asp Cys Glu Lys Lys Gly Phe Thr 35 40 45 Ser Leu Gln Arg Phe Thr AlaPro Thr Ser Gln Phe Tyr His Leu Phe 50 55 60 Leu His Gly Asn Ser Leu ThrArg Leu Phe Pro Asn Glu Phe Ala Asn 65 70 75 80 Phe Tyr Asn Ala Val SerLeu His Met Glu Asn Asn Gly Leu His Glu 85 90 95 Ile Val Pro Gly Ala PheLeu Gly Leu Gln Leu Val Lys Arg Leu His 100 105 110 Ile Asn Asn Asn LysIle Lys Ser Phe Arg Lys Gln Thr Phe Leu Gly 115 120 125 Leu Asp Asp LeuGlu Tyr Leu Gln Ala Asp Phe Asn Leu Leu Arg Asp 130 135 140 Ile Asp ProGly Ala Phe Gln Asp Leu Asn Lys Leu Glu Val Leu Ile 145 150 155 160 LeuAsn Asp Asn Leu Ile Ser Thr Leu Pro Ala Asn Val Phe Gln Tyr 165 170 175Val Pro Ile Thr His Leu Asp Leu Arg Gly Asn Arg Leu Lys Thr Leu 180 185190 Pro Tyr Glu Glu Val Leu Glu Gln Ile Pro Gly Ile Ala Glu Ile Leu 195200 205 Leu Glu Asp Asn Pro Trp Asp Cys Thr Cys Asp Leu Leu Ser Leu Lys210 215 220 Glu Trp Leu Glu Asn Ile Pro Lys Asn Ala Leu Ile Gly Arg ValVal 225 230 235 240 Cys Glu Ala Pro Thr Arg Leu Gln Gly Lys Asp Leu AsnGlu Thr Thr 245 250 255 Glu Gln Asp Leu Cys Pro Leu Lys Asn Arg Val AspSer Ser Leu Pro 260 265 270 Ala Pro Pro Ala Gln Glu Glu Thr Phe Ala ProGly Pro Leu Pro Thr 275 280 285 Pro Phe Lys Thr Asn Gly Gln Glu Asp HisAla Thr Pro Gly Ser Ala 290 295 300 Pro Asn Gly Gly Thr Lys Ile Pro GlyAsn Trp Gln Ile Lys Ile Arg 305 310 315 320 Pro Thr Ala Ala Ile Ala ThrGly Ser Ser Arg Asn Lys Pro Leu Ala 325 330 335 Asn Ser Leu Pro Cys ProGly Gly Cys Ser Cys Asp His Ile Pro Gly 340 345 350 Ser Gly Leu Lys MetAsn Cys Asn Asn Arg Asn Val Ser Ser Leu Ala 355 360 365 Asp Leu Lys ProLys Leu Ser Asn Val Gln Glu Leu Phe Leu Arg Asp 370 375 380 Asn Lys IleHis Ser Ile Arg Lys Ser His Phe Val Asp Tyr Lys Asn 385 390 395 400 LeuIle Leu Leu Asp Leu Gly Asn Asn Asn Ile Ala Thr Val Glu Asn 405 410 415Asn Thr Phe Lys Asn Leu Leu Asp Leu Arg Trp Leu Tyr Met Asp Ser 420 425430 Asn Tyr Leu Asp Thr Leu Ser Arg Glu Lys Phe Ala Gly Leu Gln Asn 435440 445 Leu Glu Tyr Leu Asn Val Glu Tyr Asn Ala Ile Gln Leu Ile Leu Pro450 455 460 Gly Thr Phe Asn Ala Met Pro Lys Leu Arg Ile Leu Ile Leu AsnAsn 465 470 475 480 Asn Leu Leu Arg Ser Leu Pro Val Asp Val Phe Ala GlyVal Ser Leu 485 490 495 Ser Lys Leu Ser Leu His Asn Asn Tyr Phe Met TyrLeu Pro Val Ala 500 505 510 Gly Val Leu Asp Gln Leu Thr Ser Ile Ile GlnIle Asp Leu His Gly 515 520 525 Asn Pro Trp Glu Cys Ser Cys Thr Ile ValPro Phe Lys Gln Trp Ala 530 535 540 Glu Arg Leu Gly Ser Glu Val Leu MetSer Asp Leu Lys Cys Glu Thr 545 550 555 560 Pro Val Asn Phe Phe Arg LysAsp Phe Met Leu Leu Ser Asn Asp Glu 565 570 575 Ile Cys Pro Gln Leu TyrAla Arg Ile Ser Pro Thr Leu Thr Ser His 580 585 590 Ser Lys Asn Ser ThrGly Leu Ala Glu Thr Gly Thr His Ser Asn Ser 595 600 605 Tyr Leu Asp ThrSer Arg Val Ser Ile Ser Val Leu Val Pro Gly Leu 610 615 620 Leu Leu ValPhe Val Thr Ser Ala Phe Thr Val Val Gly Met Leu Val 625 630 635 640 PheIle Leu Arg Asn Arg Lys Arg Ser Lys Arg Arg Asp Ala Asn Ser 645 650 655Ser Ala Ser Glu Ile Asn Ser Leu Gln Thr Val Cys Asp Ser Ser Tyr 660 665670 Trp His Asn Gly Pro Tyr Asn Ala Asp Gly Ala His Arg Val Tyr Asp 675680 685 Cys Gly Ser His Ser Leu Ser Asp 690 695 92 22 DNA ArtificialSequence Description of Artificial Sequence Synthetic oligonucleotideprobe 92 gttggatctg ggcaacaata ac 22 93 24 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe 93attgttgtgc aggctgagtt taag 24 94 45 DNA Artificial Sequence Descriptionof Artificial Sequence Synthetic oligonucleotide probe 94 ggtggctatacatggatagc aattacctgg acacgctgtc ccggg 45 95 2226 DNA Homo sapiens 95agtcgactgc gtcccctgta cccggcgcca gctgtgttcc tgaccccaga ataactcagg 60gctgcaccgg gcctggcagc gctccgcaca catttcctgt cgcggcctaa gggaaactgt 120tggccgctgg gcccgcgggg ggattcttgg cagttggggg gtccgtcggg agcgagggcg 180gaggggaagg gagggggaac cgggttgggg aagccagctg tagagggcgg tgaccgcgct 240ccagacacag ctctgcgtcc tcgagcggga cagatccaag ttgggagcag ctctgcgtgc 300ggggcctcag agaatgaggc cggcgttcgc cctgtgcctc ctctggcagg cgctctggcc 360cgggccgggc ggcggcgaac accccactgc cgaccgtgct ggctgctcgg cctcgggggc 420ctgctacagc ctgcaccacg ctaccatgaa gcggcaggcg gccgaggagg cctgcatcct 480gcgaggtggg gcgctcagca ccgtgcgtgc gggcgccgag ctgcgcgctg tgctcgcgct 540cctgcgggca ggcccagggc ccggaggggg ctccaaagac ctgctgttct gggtcgcact 600ggagcgcagg cgttcccact gcaccctgga gaacgagcct ttgcggggtt tctcctggct 660gtcctccgac cccggcggtc tcgaaagcga cacgctgcag tgggtggagg agccccaacg 720ctcctgcacc gcgcggagat gcgcggtact ccaggccacc ggtggggtcg agcccgcagg 780ctggaaggag atgcgatgcc acctgcgcgc caacggctac ctgtgcaagt accagtttga 840ggtcttgtgt cctgcgccgc gccccggggc cgcctctaac ttgagctatc gcgcgccctt 900ccagctgcac agcgccgctc tggacttcag tccacctggg accgaggtga gtgcgctctg 960ccggggacag ctcccgatct cagttacttg catcgcggac gaaatcggcg ctcgctggga 1020caaactctcg ggcgatgtgt tgtgtccctg ccccgggagg tacctccgtg ctggcaaatg 1080cgcagagctc cctaactgcc tagacgactt gggaggcttt gcctgcgaat gtgctacggg 1140cttcgagctg gggaaggacg gccgctcttg tgtgaccagt ggggaaggac agccgaccct 1200tggggggacc ggggtgccca ccaggcgccc gccggccact gcaaccagcc ccgtgccgca 1260gagaacatgg ccaatcaggg tcgacgagaa gctgggagag acaccacttg tccctgaaca 1320agacaattca gtaacatcta ttcctgagat tcctcgatgg ggatcacaga gcacgatgtc 1380tacccttcaa atgtcccttc aagccgagtc aaaggccact atcaccccat cagggagcgt 1440gatttccaag tttaattcta cgacttcctc tgccactcct caggctttcg actcctcctc 1500tgccgtggtc ttcatatttg tgagcacagc agtagtagtg ttggtgatct tgaccatgac 1560agtactgggg cttgtcaagc tctgctttca cgaaagcccc tcttcccagc caaggaagga 1620gtctatgggc ccgccgggcc tggagagtga tcctgagccc gctgctttgg gctccagttc 1680tgcacattgc acaaacaatg gggtgaaagt cggggactgt gatctgcggg acagagcaga 1740gggtgccttg ctggcggagt cccctcttgg ctctagtgat gcatagggaa acaggggaca 1800tgggcactcc tgtgaacagt ttttcacttt tgatgaaacg gggaaccaag aggaacttac 1860ttgtgtaact gacaatttct gcagaaatcc cccttcctct aaattccctt tactccactg 1920aggagctaaa tcagaactgc acactccttc cctgatgata gaggaagtgg aagtgccttt 1980aggatggtga tactggggga ccgggtagtg ctggggagag atattttctt atgtttattc 2040ggagaatttg gagaagtgat tgaacttttc aagacattgg aaacaaatag aacacaatat 2100aatttacatt aaaaaataat ttctaccaaa atggaaagga aatgttctat gttgttcagg 2160ctaggagtat attggttcga aatcccaggg aaaaaaataa aaataaaaaa ttaaaggatt 2220gttgat 2226 96 490 PRT Homo sapiens 96 Met Arg Pro Ala Phe Ala Leu CysLeu Leu Trp Gln Ala Leu Trp Pro 1 5 10 15 Gly Pro Gly Gly Gly Glu HisPro Thr Ala Asp Arg Ala Gly Cys Ser 20 25 30 Ala Ser Gly Ala Cys Tyr SerLeu His His Ala Thr Met Lys Arg Gln 35 40 45 Ala Ala Glu Glu Ala Cys IleLeu Arg Gly Gly Ala Leu Ser Thr Val 50 55 60 Arg Ala Gly Ala Glu Leu ArgAla Val Leu Ala Leu Leu Arg Ala Gly 65 70 75 80 Pro Gly Pro Gly Gly GlySer Lys Asp Leu Leu Phe Trp Val Ala Leu 85 90 95 Glu Arg Arg Arg Ser HisCys Thr Leu Glu Asn Glu Pro Leu Arg Gly 100 105 110 Phe Ser Trp Leu SerSer Asp Pro Gly Gly Leu Glu Ser Asp Thr Leu 115 120 125 Gln Trp Val GluGlu Pro Gln Arg Ser Cys Thr Ala Arg Arg Cys Ala 130 135 140 Val Leu GlnAla Thr Gly Gly Val Glu Pro Ala Gly Trp Lys Glu Met 145 150 155 160 ArgCys His Leu Arg Ala Asn Gly Tyr Leu Cys Lys Tyr Gln Phe Glu 165 170 175Val Leu Cys Pro Ala Pro Arg Pro Gly Ala Ala Ser Asn Leu Ser Tyr 180 185190 Arg Ala Pro Phe Gln Leu His Ser Ala Ala Leu Asp Phe Ser Pro Pro 195200 205 Gly Thr Glu Val Ser Ala Leu Cys Arg Gly Gln Leu Pro Ile Ser Val210 215 220 Thr Cys Ile Ala Asp Glu Ile Gly Ala Arg Trp Asp Lys Leu SerGly 225 230 235 240 Asp Val Leu Cys Pro Cys Pro Gly Arg Tyr Leu Arg AlaGly Lys Cys 245 250 255 Ala Glu Leu Pro Asn Cys Leu Asp Asp Leu Gly GlyPhe Ala Cys Glu 260 265 270 Cys Ala Thr Gly Phe Glu Leu Gly Lys Asp GlyArg Ser Cys Val Thr 275 280 285 Ser Gly Glu Gly Gln Pro Thr Leu Gly GlyThr Gly Val Pro Thr Arg 290 295 300 Arg Pro Pro Ala Thr Ala Thr Ser ProVal Pro Gln Arg Thr Trp Pro 305 310 315 320 Ile Arg Val Asp Glu Lys LeuGly Glu Thr Pro Leu Val Pro Glu Gln 325 330 335 Asp Asn Ser Val Thr SerIle Pro Glu Ile Pro Arg Trp Gly Ser Gln 340 345 350 Ser Thr Met Ser ThrLeu Gln Met Ser Leu Gln Ala Glu Ser Lys Ala 355 360 365 Thr Ile Thr ProSer Gly Ser Val Ile Ser Lys Phe Asn Ser Thr Thr 370 375 380 Ser Ser AlaThr Pro Gln Ala Phe Asp Ser Ser Ser Ala Val Val Phe 385 390 395 400 IlePhe Val Ser Thr Ala Val Val Val Leu Val Ile Leu Thr Met Thr 405 410 415Val Leu Gly Leu Val Lys Leu Cys Phe His Glu Ser Pro Ser Ser Gln 420 425430 Pro Arg Lys Glu Ser Met Gly Pro Pro Gly Leu Glu Ser Asp Pro Glu 435440 445 Pro Ala Ala Leu Gly Ser Ser Ser Ala His Cys Thr Asn Asn Gly Val450 455 460 Lys Val Gly Asp Cys Asp Leu Arg Asp Arg Ala Glu Gly Ala LeuLeu 465 470 475 480 Ala Glu Ser Pro Leu Gly Ser Ser Asp Ala 485 490 9724 DNA Artificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 97 tggaaggaga tgcgatgcca cctg 24 98 20 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 98 tgaccagtgg ggaaggacag 20 99 20 DNA ArtificialSequence Description of Artificial Sequence Synthetic oligonucleotideprobe 99 acagagcaga gggtgccttg 20 100 24 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe 100tcagggacaa gtggtgtctc tccc 24 101 24 DNA Artificial Sequence Descriptionof Artificial Sequence Synthetic oligonucleotide probe 101 tcagggaaggagtgtgcagt tctg 24 102 50 DNA Artificial Sequence Description ofArtificial Sequence Synthetic oligonucleotide probe 102 acagctcccgatctcagtta cttgcatcgc ggacgaaatc ggcgctcgct 50 103 2026 DNA Homo sapiens103 cggacgcgtg ggattcagca gtggcctgtg gctgccagag cagctcctca ggggaaacta 60agcgtcgagt cagacggcac cataatcgcc tttaaaagtg cctccgccct gccggccgcg 120tatcccccgg ctacctgggc cgccccgcgg cggtgcgcgc gtgagaggga gcgcgcgggc 180agccgagcgc cggtgtgagc cagcgctgct gccagtgtga gcggcggtgt gagcgcggtg 240ggtgcggagg ggcgtgtgtg ccggcgcgcg cgccgtgggg tgcaaacccc gagcgtctac 300gctgccatga ggggcgcgaa cgcctgggcg ccactctgcc tgctgctggc tgccgccacc 360cagctctcgc ggcagcagtc cccagagaga cctgttttca catgtggtgg cattcttact 420ggagagtctg gatttattgg cagtgaaggt tttcctggag tgtaccctcc aaatagcaaa 480tgtacttgga aaatcacagt tcccgaagga aaagtagtcg ttctcaattt ccgattcata 540gacctcgaga gtgacaacct gtgccgctat gactttgtgg atgtgtacaa tggccatgcc 600aatggccagc gcattggccg cttctgtggc actttccggc ctggagccct tgtgtccagt 660ggcaacaaga tgatggtgca gatgatttct gatgccaaca cagctggcaa tggcttcatg 720gccatgttct ccgctgctga accaaacgaa agaggggatc agtattgtgg aggactcctt 780gacagacctt ccggctcttt taaaaccccc aactggccag accgggatta ccctgcagga 840gtcacttgtg tgtggcacat tgtagcccca aagaatcagc ttatagaatt aaagtttgag 900aagtttgatg tggagcgaga taactactgc cgatatgatt atgtggctgt gtttaatggc 960ggggaagtca acgatgctag aagaattgga aagtattgtg gtgatagtcc acctgcgcca 1020attgtgtctg agagaaatga acttcttatt cagtttttat cagacttaag tttaactgca 1080gatgggttta ttggtcacta catattcagg ccaaaaaaac tgcctacaac tacagaacag 1140cctgtcacca ccacattccc tgtaaccacg ggtttaaaac ccaccgtggc cttgtgtcaa 1200caaaagtgta gacggacggg gactctggag ggcaattatt gttcaagtga ctttgtatta 1260gccggcactg ttatcacaac catcactcgc gatgggagtt tgcacgccac agtctcgatc 1320atcaacatct acaaagaggg aaatttggcg attcagcagg cgggcaagaa catgagtgcc 1380aggctgactg tcgtctgcaa gcagtgccct ctcctcagaa gaggtctaaa ttacattatt 1440atgggccaag taggtgaaga tgggcgaggc aaaatcatgc caaacagctt tatcatgatg 1500ttcaagacca agaatcagaa gctcctggat gccttaaaaa ataagcaatg ttaacagtga 1560actgtgtcca tttaagctgt attctgccat tgcctttgaa agatctatgt tctctcagta 1620gaaaaaaaaa tacttataaa attacatatt ctgaaagagg attccgaaag atgggactgg 1680ttgactcttc acatgatgga ggtatgaggc ctccgagata gctgagggaa gttctttgcc 1740tgctgtcaga ggagcagcta tctgattgga aacctgccga cttagtgcgg tgataggaag 1800ctaaaagtgt caagcgttga cagcttggaa gcgtttattt atacatctct gtaaaaggat 1860attttagaat tgagttgtgt gaagatgtca aaaaaagatt ttagaagtgc aatatttata 1920gtgttatttg tttcaccttc aagcctttgc cctgaggtgt tacaatcttg tcttgcgttt 1980tctaaatcaa tgcttaataa aatattttta aaggaaaaaa aaaaaa 2026 104 415 PRT Homosapiens 104 Met Arg Gly Ala Asn Ala Trp Ala Pro Leu Cys Leu Leu Leu AlaAla 1 5 10 15 Ala Thr Gln Leu Ser Arg Gln Gln Ser Pro Glu Arg Pro ValPhe Thr 20 25 30 Cys Gly Gly Ile Leu Thr Gly Glu Ser Gly Phe Ile Gly SerGlu Gly 35 40 45 Phe Pro Gly Val Tyr Pro Pro Asn Ser Lys Cys Thr Trp LysIle Thr 50 55 60 Val Pro Glu Gly Lys Val Val Val Leu Asn Phe Arg Phe IleAsp Leu 65 70 75 80 Glu Ser Asp Asn Leu Cys Arg Tyr Asp Phe Val Asp ValTyr Asn Gly 85 90 95 His Ala Asn Gly Gln Arg Ile Gly Arg Phe Cys Gly ThrPhe Arg Pro 100 105 110 Gly Ala Leu Val Ser Ser Gly Asn Lys Met Met ValGln Met Ile Ser 115 120 125 Asp Ala Asn Thr Ala Gly Asn Gly Phe Met AlaMet Phe Ser Ala Ala 130 135 140 Glu Pro Asn Glu Arg Gly Asp Gln Tyr CysGly Gly Leu Leu Asp Arg 145 150 155 160 Pro Ser Gly Ser Phe Lys Thr ProAsn Trp Pro Asp Arg Asp Tyr Pro 165 170 175 Ala Gly Val Thr Cys Val TrpHis Ile Val Ala Pro Lys Asn Gln Leu 180 185 190 Ile Glu Leu Lys Phe GluLys Phe Asp Val Glu Arg Asp Asn Tyr Cys 195 200 205 Arg Tyr Asp Tyr ValAla Val Phe Asn Gly Gly Glu Val Asn Asp Ala 210 215 220 Arg Arg Ile GlyLys Tyr Cys Gly Asp Ser Pro Pro Ala Pro Ile Val 225 230 235 240 Ser GluArg Asn Glu Leu Leu Ile Gln Phe Leu Ser Asp Leu Ser Leu 245 250 255 ThrAla Asp Gly Phe Ile Gly His Tyr Ile Phe Arg Pro Lys Lys Leu 260 265 270Pro Thr Thr Thr Glu Gln Pro Val Thr Thr Thr Phe Pro Val Thr Thr 275 280285 Gly Leu Lys Pro Thr Val Ala Leu Cys Gln Gln Lys Cys Arg Arg Thr 290295 300 Gly Thr Leu Glu Gly Asn Tyr Cys Ser Ser Asp Phe Val Leu Ala Gly305 310 315 320 Thr Val Ile Thr Thr Ile Thr Arg Asp Gly Ser Leu His AlaThr Val 325 330 335 Ser Ile Ile Asn Ile Tyr Lys Glu Gly Asn Leu Ala IleGln Gln Ala 340 345 350 Gly Lys Asn Met Ser Ala Arg Leu Thr Val Val CysLys Gln Cys Pro 355 360 365 Leu Leu Arg Arg Gly Leu Asn Tyr Ile Ile MetGly Gln Val Gly Glu 370 375 380 Asp Gly Arg Gly Lys Ile Met Pro Asn SerPhe Ile Met Met Phe Lys 385 390 395 400 Thr Lys Asn Gln Lys Leu Leu AspAla Leu Lys Asn Lys Gln Cys 405 410 415 105 22 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe 105106 22 DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 106 107 45 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe 107108 1838 DNA Homo sapiens 108 cggacgcgtg ggcggacgcg tgggcggcccacggcgcccg cgggctgggg cggtcgcttc 60 ttccttctcc gtggcctacg agggtccccagcctgggtaa agatggcccc atggcccccg 120 aagggcctag tcccagctgt gctctggggcctcagcctct tcctcaacct cccaggacct 180 atctggctcc agccctctcc acctccccagtcttctcccc cgcctcagcc ccatccgtgt 240 catacctgcc ggggactggt tgacagctttaacaagggcc tggagagaac catccgggac 300 aactttggag gtggaaacac tgcctgggaggaagagaatt tgtccaaata caaagacagt 360 gagacccgcc tggtagaggt gctggagggtgtgtgcagca agtcagactt cgagtgccac 420 cgcctgctgg agctgagtga ggagctggtggagagctggt ggtttcacaa gcagcaggag 480 gccccggacc tcttccagtg gctgtgctcagattccctga agctctgctg ccccgcaggc 540 accttcgggc cctcctgcct tccctgtcctgggggaacag agaggccctg cggtggctac 600 gggcagtgtg aaggagaagg gacacgagggggcagcgggc actgtgactg ccaagccggc 660 tacgggggtg aggcctgtgg ccagtgtggccttggctact ttgaggcaga acgcaacgcc 720 agccatctgg tatgttcggc ttgttttggcccctgtgccc gatgctcagg acctgaggaa 780 tcaaactgtt tgcaatgcaa gaagggctgggccctgcatc acctcaagtg tgtagacatt 840 gatgagtgtg gcacagaggg agccaactgtggagctgacc aattctgcgt gaacactgag 900 ggctcctatg agtgccgaga ctgtgccaaggcctgcctag gctgcatggg ggcagggcca 960 ggtcgctgta agaagtgtag ccctggctatcagcaggtgg gctccaagtg tctcgatgtg 1020 gatgagtgtg agacagaggt gtgtccgggagagaacaagc agtgtgaaaa caccgagggc 1080 ggttatcgct gcatctgtgc cgagggctacaagcagatgg aaggcatctg tgtgaaggag 1140 cagatcccag agtcagcagg cttcttctcagagatgacag aagacgagtt ggtggtgctg 1200 cagcagatgt tctttggcat catcatctgtgcactggcca cgctggctgc taagggcgac 1260 ttggtgttca ccgccatctt cattggggctgtggcggcca tgactggcta ctggttgtca 1320 gagcgcagtg accgtgtgct ggagggcttcatcaagggca gataatcgcg gccaccacct 1380 gtaggacctc ctcccaccca cgctgcccccagagcttggg ctgccctcct gctggacact 1440 caggacagct tggtttattt ttgagagtggggtaagcacc cctacctgcc ttacagagca 1500 gcccaggtac ccaggcccgg gcagacaaggcccctggggt aaaaagtagc cctgaaggtg 1560 gataccatga gctcttcacc tggcggggactggcaggctt cacaatgtgt gaatttcaaa 1620 agtttttcct taatggtggc tgctagagctttggcccctg cttaggatta ggtggtcctc 1680 acaggggtgg ggccatcaca gctccctcctgccagctgca tgctgccagt tcctgttctg 1740 tgttcaccac atccccacac cccattgccacttatttatt catctcagga aataaagaaa 1800 ggtcttggaa agttaaaaaa aaaaaaaaaaaaaaaaaa 1838 109 420 PRT Homo sapiens 109 Met Ala Pro Trp Pro Pro LysGly Leu Val Pro Ala Val Leu Trp Gly 1 5 10 15 Leu Ser Leu Phe Leu AsnLeu Pro Gly Pro Ile Trp Leu Gln Pro Ser 20 25 30 Pro Pro Pro Gln Ser SerPro Pro Pro Gln Pro His Pro Cys His Thr 35 40 45 Cys Arg Gly Leu Val AspSer Phe Asn Lys Gly Leu Glu Arg Thr Ile 50 55 60 Arg Asp Asn Phe Gly GlyGly Asn Thr Ala Trp Glu Glu Glu Asn Leu 65 70 75 80 Ser Lys Tyr Lys AspSer Glu Thr Arg Leu Val Glu Val Leu Glu Gly 85 90 95 Val Cys Ser Lys SerAsp Phe Glu Cys His Arg Leu Leu Glu Leu Ser 100 105 110 Glu Glu Leu ValGlu Ser Trp Trp Phe His Lys Gln Gln Glu Ala Pro 115 120 125 Asp Leu PheGln Trp Leu Cys Ser Asp Ser Leu Lys Leu Cys Cys Pro 130 135 140 Ala GlyThr Phe Gly Pro Ser Cys Leu Pro Cys Pro Gly Gly Thr Glu 145 150 155 160Arg Pro Cys Gly Gly Tyr Gly Gln Cys Glu Gly Glu Gly Thr Arg Gly 165 170175 Gly Ser Gly His Cys Asp Cys Gln Ala Gly Tyr Gly Gly Glu Ala Cys 180185 190 Gly Gln Cys Gly Leu Gly Tyr Phe Glu Ala Glu Arg Asn Ala Ser His195 200 205 Leu Val Cys Ser Ala Cys Phe Gly Pro Cys Ala Arg Cys Ser GlyPro 210 215 220 Glu Glu Ser Asn Cys Leu Gln Cys Lys Lys Gly Trp Ala LeuHis His 225 230 235 240 Leu Lys Cys Val Asp Ile Asp Glu Cys Gly Thr GluGly Ala Asn Cys 245 250 255 Gly Ala Asp Gln Phe Cys Val Asn Thr Glu GlySer Tyr Glu Cys Arg 260 265 270 Asp Cys Ala Lys Ala Cys Leu Gly Cys MetGly Ala Gly Pro Gly Arg 275 280 285 Cys Lys Lys Cys Ser Pro Gly Tyr GlnGln Val Gly Ser Lys Cys Leu 290 295 300 Asp Val Asp Glu Cys Glu Thr GluVal Cys Pro Gly Glu Asn Lys Gln 305 310 315 320 Cys Glu Asn Thr Glu GlyGly Tyr Arg Cys Ile Cys Ala Glu Gly Tyr 325 330 335 Lys Gln Met Glu GlyIle Cys Val Lys Glu Gln Ile Pro Glu Ser Ala 340 345 350 Gly Phe Phe SerGlu Met Thr Glu Asp Glu Leu Val Val Leu Gln Gln 355 360 365 Met Phe PheGly Ile Ile Ile Cys Ala Leu Ala Thr Leu Ala Ala Lys 370 375 380 Gly AspLeu Val Phe Thr Ala Ile Phe Ile Gly Ala Val Ala Ala Met 385 390 395 400Thr Gly Tyr Trp Leu Ser Glu Arg Ser Asp Arg Val Leu Glu Gly Phe 405 410415 Ile Lys Gly Arg 420 110 50 DNA Artificial Sequence Description ofArtificial Sequence Synthetic oligonucleotide probe 110 cctggctatcagcaggtggg ctccaagtgt ctcgatgtgg atgagtgtga 50 111 22 DNA ArtificialSequence Description of Artificial Sequence Synthetic oligonucleotideprobe 111 attctgcgtg aacactgagg gc 22 112 22 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe 112atctgcttgt agccctcggc ac 22 113 1616 DNA Homo sapiens modified_base(1461) a, t, c or g 113 tgagaccctc ctgcagcctt ctcaagggac agccccactctgcctcttgc tcctccaggg 60 cagcaccatg cagcccctgt ggctctgctg ggcactctgggtgttgcccc tggccagccc 120 cggggccgcc ctgaccgggg agcagctcct gggcagcctgctgcggcagc tgcagctcaa 180 agaggtgccc accctggaca gggccgacat ggaggagctggtcatcccca cccacgtgag 240 ggcccagtac gtggccctgc tgcagcgcag ccacggggaccgctcccgcg gaaagaggtt 300 cagccagagc ttccgagagg tggccggcag gttcctggcgttggaggcca gcacacacct 360 gctggtgttc ggcatggagc agcggctgcc gcccaacagcgagctggtgc aggccgtgct 420 gcggctcttc caggagccgg tccccaaggc cgcgctgcacaggcacgggc ggctgtcccc 480 gcgcagcgcc cgggcccggg tgaccgtcga gtggctgcgcgtccgcgacg acggctccaa 540 ccgcacctcc ctcatcgact ccaggctggt gtccgtccacgagagcggct ggaaggcctt 600 cgacgtgacc gaggccgtga acttctggca gcagctgagccggccccggc agccgctgct 660 gctacaggtg tcggtgcaga gggagcatct gggcccgctggcgtccggcg cccacaagct 720 ggtccgcttt gcctcgcagg gggcgccagc cgggcttggggagccccagc tggagctgca 780 caccctggac cttggggact atggagctca gggcgactgtgaccctgaag caccaatgac 840 cgagggcacc cgctgctgcc gccaggagat gtacattgacctgcagggga tgaagtgggc 900 cgagaactgg gtgctggagc ccccgggctt cctggcttatgagtgtgtgg gcacctgccg 960 gcagcccccg gaggccctgg ccttcaagtg gccgtttctggggcctcgac agtgcatcgc 1020 ctcggagact gactcgctgc ccatgatcgt cagcatcaaggagggaggca ggaccaggcc 1080 ccaggtggtc agcctgccca acatgagggt gcagaagtgcagctgtgcct cggatggtgc 1140 gctcgtgcca aggaggctcc agccataggc gcctagtgtagccatcgagg gacttgactt 1200 gtgtgtgttt ctgaagtgtt cgagggtacc aggagagctggcgatgactg aactgctgat 1260 ggacaaatgc tctgtgctct ctagtgagcc ctgaatttgcttcctctgac aagttacctc 1320 acctaatttt tgcttctcag gaatgagaat ctttggccactggagagccc ttgctcagtt 1380 ttctctattc ttattattca ctgcactata ttctaagcacttacatgtgg agatactgta 1440 acctgagggc agaaagccca ntgtgtcatt gtttacttgtcctgtcactg gatctgggct 1500 aaagtcctcc accaccactc tggacctaag acctggggttaagtgtgggt tgtgcatccc 1560 caatccagat aataaagact ttgtaaaaca tgaataaaacacattttatt ctaaaa 1616 114 366 PRT Homo sapiens 114 Met Gln Pro Leu TrpLeu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala 1 5 10 15 Ser Pro Gly AlaAla Leu Thr Gly Glu Gln Leu Leu Gly Ser Leu Leu 20 25 30 Arg Gln Leu GlnLeu Lys Glu Val Pro Thr Leu Asp Arg Ala Asp Met 35 40 45 Glu Glu Leu ValIle Pro Thr His Val Arg Ala Gln Tyr Val Ala Leu 50 55 60 Leu Gln Arg SerHis Gly Asp Arg Ser Arg Gly Lys Arg Phe Ser Gln 65 70 75 80 Ser Phe ArgGlu Val Ala Gly Arg Phe Leu Ala Leu Glu Ala Ser Thr 85 90 95 His Leu LeuVal Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu 100 105 110 Leu ValGln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala 115 120 125 AlaLeu His Arg His Gly Arg Leu Ser Pro Arg Ser Ala Arg Ala Arg 130 135 140Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr 145 150155 160 Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys165 170 175 Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu SerArg 180 185 190 Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg GluHis Leu 195 200 205 Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg PheAla Ser Gln 210 215 220 Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu GluLeu His Thr Leu 225 230 235 240 Asp Leu Gly Asp Tyr Gly Ala Gln Gly AspCys Asp Pro Glu Ala Pro 245 250 255 Met Thr Glu Gly Thr Arg Cys Cys ArgGln Glu Met Tyr Ile Asp Leu 260 265 270 Gln Gly Met Lys Trp Ala Glu AsnTrp Val Leu Glu Pro Pro Gly Phe 275 280 285 Leu Ala Tyr Glu Cys Val GlyThr Cys Arg Gln Pro Pro Glu Ala Leu 290 295 300 Ala Phe Lys Trp Pro PheLeu Gly Pro Arg Gln Cys Ile Ala Ser Glu 305 310 315 320 Thr Asp Ser LeuPro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr 325 330 335 Arg Pro GlnVal Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser 340 345 350 Cys AlaSer Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro 355 360 365 115 21 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 115 aggactgcca taacttgcct g 21 116 22 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 116 ataggagttg aagcagcgct gc 22 117 45 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 117 tgtgtggaca tagacgagtg ccgctaccgc tactgccagcaccgc 45 118 1857 DNA Homo sapiens 118 gtctgttccc aggagtcctt cggcggctgttgtgtcagtg gcctgatcgc gatggggaca 60 aaggcgcaag tcgagaggaa actgttgtgcctcttcatat tggcgatcct gttgtgctcc 120 ctggcattgg gcagtgttac agtgcactcttctgaacctg aagtcagaat tcctgagaat 180 aatcctgtga agttgtcctg tgcctactcgggcttttctt ctccccgtgt ggagtggaag 240 tttgaccaag gagacaccac cagactcgtttgctataata acaagatcac agcttcctat 300 gaggaccggg tgaccttctt gccaactggtatcaccttca agtccgtgac acgggaagac 360 actgggacat acacttgtat ggtctctgaggaaggcggca acagctatgg ggaggtcaag 420 gtcaagctca tcgtgcttgt gcctccatccaagcctacag ttaacatccc ctcctctgcc 480 accattggga accgggcagt gctgacatgctcagaacaag atggttcccc accttctgaa 540 tacacctggt tcaaagatgg gatagtgatgcctacgaatc ccaaaagcac ccgtgccttc 600 agcaactctt cctatgtcct gaatcccacaacaggagagc tggtctttga tcccctgtca 660 gcctctgata ctggagaata cagctgtgaggcacggaatg ggtatgggac acccatgact 720 tcaaatgctg tgcgcatgga agctgtggagcggaatgtgg gggtcatcgt ggcagccgtc 780 cttgtaaccc tgattctcct gggaatcttggtttttggca tctggtttgc ctatagccga 840 ggccactttg acagaacaaa gaaagggacttcgagtaaga aggtgattta cagccagcct 900 agtgcccgaa gtgaaggaga attcaaacagacctcgtcat tcctggtgtg agcctggtcg 960 gctcaccgcc tatcatctgc atttgccttactcaggtgct accggactct ggcccctgat 1020 gtctgtagtt tcacaggatg ccttatttgtcttctacacc ccacagggcc ccctacttct 1080 tcggatgtgt ttttaataat gtcagctatgtgccccatcc tccttcatgc cctccctccc 1140 tttcctacca ctgctgagtg gcctggaacttgtttaaagt gtttattccc catttctttg 1200 agggatcagg aaggaatcct gggtatgccattgacttccc ttctaagtag acagcaaaaa 1260 tggcgggggt cgcaggaatc tgcactcaactgcccacctg gctggcaggg atctttgaat 1320 aggtatcttg agcttggttc tgggctctttccttgtgtac tgacgaccag ggccagctgt 1380 tctagagcgg gaattagagg ctagagcggctgaaatggtt gtttggtgat gacactgggg 1440 tccttccatc tctggggccc actctcttctgtcttcccat gggaagtgcc actgggatcc 1500 ctctgccctg tcctcctgaa tacaagctgactgacattga ctgtgtctgt ggaaaatggg 1560 agctcttgtt gtggagagca tagtaaattttcagagaact tgaagccaaa aggatttaaa 1620 accgctgctc taaagaaaag aaaactggaggctgggcgca gtggctcacg cctgtaatcc 1680 cagaggctga ggcaggcgga tcacctgaggtcgggagttc gggatcagcc tgaccaacat 1740 ggagaaaccc tactggaaat acaaagttagccaggcatgg tggtgcatgc ctgtagtccc 1800 agctgctcag gagcctggca acaagagcaaaactccagct caaaaaaaaa aaaaaaa 1857 119 299 PRT Homo sapiens 119 Met GlyThr Lys Ala Gln Val Glu Arg Lys Leu Leu Cys Leu Phe Ile 1 5 10 15 LeuAla Ile Leu Leu Cys Ser Leu Ala Leu Gly Ser Val Thr Val His 20 25 30 SerSer Glu Pro Glu Val Arg Ile Pro Glu Asn Asn Pro Val Lys Leu 35 40 45 SerCys Ala Tyr Ser Gly Phe Ser Ser Pro Arg Val Glu Trp Lys Phe 50 55 60 AspGln Gly Asp Thr Thr Arg Leu Val Cys Tyr Asn Asn Lys Ile Thr 65 70 75 80Ala Ser Tyr Glu Asp Arg Val Thr Phe Leu Pro Thr Gly Ile Thr Phe 85 90 95Lys Ser Val Thr Arg Glu Asp Thr Gly Thr Tyr Thr Cys Met Val Ser 100 105110 Glu Glu Gly Gly Asn Ser Tyr Gly Glu Val Lys Val Lys Leu Ile Val 115120 125 Leu Val Pro Pro Ser Lys Pro Thr Val Asn Ile Pro Ser Ser Ala Thr130 135 140 Ile Gly Asn Arg Ala Val Leu Thr Cys Ser Glu Gln Asp Gly SerPro 145 150 155 160 Pro Ser Glu Tyr Thr Trp Phe Lys Asp Gly Ile Val MetPro Thr Asn 165 170 175 Pro Lys Ser Thr Arg Ala Phe Ser Asn Ser Ser TyrVal Leu Asn Pro 180 185 190 Thr Thr Gly Glu Leu Val Phe Asp Pro Leu SerAla Ser Asp Thr Gly 195 200 205 Glu Tyr Ser Cys Glu Ala Arg Asn Gly TyrGly Thr Pro Met Thr Ser 210 215 220 Asn Ala Val Arg Met Glu Ala Val GluArg Asn Val Gly Val Ile Val 225 230 235 240 Ala Ala Val Leu Val Thr LeuIle Leu Leu Gly Ile Leu Val Phe Gly 245 250 255 Ile Trp Phe Ala Tyr SerArg Gly His Phe Asp Arg Thr Lys Lys Gly 260 265 270 Thr Ser Ser Lys LysVal Ile Tyr Ser Gln Pro Ser Ala Arg Ser Glu 275 280 285 Gly Glu Phe LysGln Thr Ser Ser Phe Leu Val 290 295 120 24 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe 120tcgcggagct gtgttctgtt tccc 24 121 50 DNA Artificial Sequence Descriptionof Artificial Sequence Synthetic oligonucleotide probe 121 tgatcgcgatggggacaaag gcgcaagctc gagaggaaac tgttgtgcct 50 122 20 DNA ArtificialSequence Description of Artificial Sequence Synthetic oligonucleotideprobe 122 acacctggtt caaagatggg 20 123 24 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe 123taggaagagt tgctgaaggc acgg 24 124 20 DNA Artificial Sequence Descriptionof Artificial Sequence Synthetic oligonucleotide probe 124 ttgccttactcaggtgctac 20 125 20 DNA Artificial Sequence Description of ArtificialSequence Synthetic oligonucleotide probe 125 actcagcagt ggtaggaaag 20126 1210 DNA Homo sapiens 126 cagcgcgtgg ccggcgccgc tgtggggacagcatgagcgg cggttggatg gcgcaggttg 60 gagcgtggcg aacaggggct ctgggcctggcgctgctgct gctgctcggc ctcggactag 120 gcctggaggc cgccgcgagc ccgctttccaccccgacctc tgcccaggcc gcaggcccca 180 gctcaggctc gtgcccaccc accaagttccagtgccgcac cagtggctta tgcgtgcccc 240 tcacctggcg ctgcgacagg gacttggactgcagcgatgg cagcgatgag gaggagtgca 300 ggattgagcc atgtacccag aaagggcaatgcccaccgcc ccctggcctc ccctgcccct 360 gcaccggcgt cagtgactgc tctgggggaactgacaagaa actgcgcaac tgcagccgcc 420 tggcctgcct agcaggcgag ctccgttgcacgctgagcga tgactgcatt ccactcacgt 480 ggcgctgcga cggccaccca gactgtcccgactccagcga cgagctcggc tgtggaacca 540 atgagatcct cccggaaggg gatgccacaaccatggggcc ccctgtgacc ctggagagtg 600 tcacctctct caggaatgcc acaaccatggggccccctgt gaccctggag agtgtcccct 660 ctgtcgggaa tgccacatcc tcctctgccggagaccagtc tggaagccca actgcctatg 720 gggttattgc agctgctgcg gtgctcagtgcaagcctggt caccgccacc ctcctccttt 780 tgtcctggct ccgagcccag gagcgcctccgcccactggg gttactggtg gccatgaagg 840 agtccctgct gctgtcagaa cagaagacctcgctgccctg aggacaagca cttgccacca 900 ccgtcactca gccctgggcg tagccggacaggaggagagc agtgatgcgg atgggtaccc 960 gggcacacca gccctcagag acctgagttcttctggccac gtggaacctc gaacccgagc 1020 tcctgcagaa gtggccctgg agattgagggtccctggaca ctccctatgg agatccgggg 1080 agctaggatg gggaacctgc cacagccagaactgaggggc tggccccagg cagctcccag 1140 ggggtagaac ggccctgtgc ttaagacactccctgctgcc ccgtctgagg gtggcgatta 1200 aagttgcttc 1210 127 282 PRT Homosapiens 127 Met Ser Gly Gly Trp Met Ala Gln Val Gly Ala Trp Arg Thr GlyAla 1 5 10 15 Leu Gly Leu Ala Leu Leu Leu Leu Leu Gly Leu Gly Leu GlyLeu Glu 20 25 30 Ala Ala Ala Ser Pro Leu Ser Thr Pro Thr Ser Ala Gln AlaAla Gly 35 40 45 Pro Ser Ser Gly Ser Cys Pro Pro Thr Lys Phe Gln Cys ArgThr Ser 50 55 60 Gly Leu Cys Val Pro Leu Thr Trp Arg Cys Asp Arg Asp LeuAsp Cys 65 70 75 80 Ser Asp Gly Ser Asp Glu Glu Glu Cys Arg Ile Glu ProCys Thr Gln 85 90 95 Lys Gly Gln Cys Pro Pro Pro Pro Gly Leu Pro Cys ProCys Thr Gly 100 105 110 Val Ser Asp Cys Ser Gly Gly Thr Asp Lys Lys LeuArg Asn Cys Ser 115 120 125 Arg Leu Ala Cys Leu Ala Gly Glu Leu Arg CysThr Leu Ser Asp Asp 130 135 140 Cys Ile Pro Leu Thr Trp Arg Cys Asp GlyHis Pro Asp Cys Pro Asp 145 150 155 160 Ser Ser Asp Glu Leu Gly Cys GlyThr Asn Glu Ile Leu Pro Glu Gly 165 170 175 Asp Ala Thr Thr Met Gly ProPro Val Thr Leu Glu Ser Val Thr Ser 180 185 190 Leu Arg Asn Ala Thr ThrMet Gly Pro Pro Val Thr Leu Glu Ser Val 195 200 205 Pro Ser Val Gly AsnAla Thr Ser Ser Ser Ala Gly Asp Gln Ser Gly 210 215 220 Ser Pro Thr AlaTyr Gly Val Ile Ala Ala Ala Ala Val Leu Ser Ala 225 230 235 240 Ser LeuVal Thr Ala Thr Leu Leu Leu Leu Ser Trp Leu Arg Ala Gln 245 250 255 GluArg Leu Arg Pro Leu Gly Leu Leu Val Ala Met Lys Glu Ser Leu 260 265 270Leu Leu Ser Glu Gln Lys Thr Ser Leu Pro 275 280 128 24 DNA ArtificialSequence Description of Artificial Sequence Synthetic oligonucleotideprobe 128 aagttccagt gccgcaccag tggc 24 129 24 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe 129ttggttccac agccgagctc gtcg 24 130 50 DNA Artificial Sequence Descriptionof Artificial Sequence Synthetic oligonucleotide probe 130 gaggaggagtgcaggattga gccatgtacc cagaaagggc aatgcccacc 50 131 1843 DNA Homo sapiensmodified_base (1837) a, t, c or g 131 cccacgcgtc cggtctcgct cgctcgcgcagcggcggcag cagaggtcgc gcacagatgc 60 gggttagact ggcgggggga ggaggcggaggagggaagga agctgcatgc atgagaccca 120 cagactcttg caagctggat gccctctgtggatgaaagat gtatcatgga atgaacccga 180 gcaatggaga tggatttcta gagcagcagcagcagcagca gcaacctcag tccccccaga 240 gactcttggc cgtgatcctg tggtttcagctggcgctgtg cttcggccct gcacagctca 300 cgggcgggtt cgatgacctt caagtgtgtgctgaccccgg cattcccgag aatggcttca 360 ggacccccag cggaggggtt ttctttgaaggctctgtagc ccgatttcac tgccaagacg 420 gattcaagct gaagggcgct acaaagagactgtgtttgaa gcattttaat ggaaccctag 480 gctggatccc aagtgataat tccatctgtgtgcaagaaga ttgccgtatc cctcaaatcg 540 aagatgctga gattcataac aagacatatagacatggaga gaagctaatc atcacttgtc 600 atgaaggatt caagatccgg taccccgacctacacaatat ggtttcatta tgtcgcgatg 660 atggaacgtg gaataatctg cccatctgtcaaggctgcct gagacctcta gcctcttcta 720 atggctatgt aaacatctct gagctccagacctccttccc ggtggggact gtgatctcct 780 atcgctgctt tcccggattt aaacttgatgggtctgcgta tcttgagtgc ttacaaaacc 840 ttatctggtc gtccagccca ccccggtgccttgctctgga agcccaagtc tgtccactac 900 ctccaatggt gagtcacgga gatttcgtctgccacccgcg gccttgtgag cgctacaacc 960 acggaactgt ggtggagttt tactgcgatcctggctacag cctcaccagc gactacaagt 1020 acatcacctg ccagtatgga gagtggtttccttcttatca agtctactgc atcaaatcag 1080 agcaaacgtg gcccagcacc catgagaccctcctgaccac gtggaagatt gtggcgttca 1140 cggcaaccag tgtgctgctg gtgctgctgctcgtcatcct ggccaggatg ttccagacca 1200 agttcaaggc ccactttccc cccagggggcctccccggag ttccagcagt gaccctgact 1260 ttgtggtggt agacggcgtg cccgtcatgctcccgtccta tgacgaagct gtgagtggcg 1320 gcttgagtgc cttaggcccc gggtacatggcctctgtggg ccagggctgc cccttacccg 1380 tggacgacca gagcccccca gcataccccggctcagggga cacggacaca ggcccagggg 1440 agtcagaaac ctgtgacagc gtctcaggctcttctgagct gctccaaagt ctgtattcac 1500 ctcccaggtg ccaagagagc acccaccctgcttcggacaa ccctgacata attgccagca 1560 cggcagagga ggtggcatcc accagcccaggcatccatca tgcccactgg gtgttgttcc 1620 taagaaactg attgattaaa aaatttcccaaagtgtcctg aagtgtctct tcaaatacat 1680 gttgatctgt ggagttgatt cctttccttctcttggtttt agacaaatgt aaacaaagct 1740 ctgatcctta aaattgctat gctgatagagtggtgagggc tggaagcttg atcaagtcct 1800 gtttcttctt gacacagact gattaaaaattaaaagnaaa aaa 1843 132 490 PRT Homo sapiens 132 Met Tyr His Gly Met AsnPro Ser Asn Gly Asp Gly Phe Leu Glu Gln 1 5 10 15 Gln Gln Gln Gln GlnGln Pro Gln Ser Pro Gln Arg Leu Leu Ala Val 20 25 30 Ile Leu Trp Phe GlnLeu Ala Leu Cys Phe Gly Pro Ala Gln Leu Thr 35 40 45 Gly Gly Phe Asp AspLeu Gln Val Cys Ala Asp Pro Gly Ile Pro Glu 50 55 60 Asn Gly Phe Arg ThrPro Ser Gly Gly Val Phe Phe Glu Gly Ser Val 65 70 75 80 Ala Arg Phe HisCys Gln Asp Gly Phe Lys Leu Lys Gly Ala Thr Lys 85 90 95 Arg Leu Cys LeuLys His Phe Asn Gly Thr Leu Gly Trp Ile Pro Ser 100 105 110 Asp Asn SerIle Cys Val Gln Glu Asp Cys Arg Ile Pro Gln Ile Glu 115 120 125 Asp AlaGlu Ile His Asn Lys Thr Tyr Arg His Gly Glu Lys Leu Ile 130 135 140 IleThr Cys His Glu Gly Phe Lys Ile Arg Tyr Pro Asp Leu His Asn 145 150 155160 Met Val Ser Leu Cys Arg Asp Asp Gly Thr Trp Asn Asn Leu Pro Ile 165170 175 Cys Gln Gly Cys Leu Arg Pro Leu Ala Ser Ser Asn Gly Tyr Val Asn180 185 190 Ile Ser Glu Leu Gln Thr Ser Phe Pro Val Gly Thr Val Ile SerTyr 195 200 205 Arg Cys Phe Pro Gly Phe Lys Leu Asp Gly Ser Ala Tyr LeuGlu Cys 210 215 220 Leu Gln Asn Leu Ile Trp Ser Ser Ser Pro Pro Arg CysLeu Ala Leu 225 230 235 240 Glu Ala Gln Val Cys Pro Leu Pro Pro Met ValSer His Gly Asp Phe 245 250 255 Val Cys His Pro Arg Pro Cys Glu Arg TyrAsn His Gly Thr Val Val 260 265 270 Glu Phe Tyr Cys Asp Pro Gly Tyr SerLeu Thr Ser Asp Tyr Lys Tyr 275 280 285 Ile Thr Cys Gln Tyr Gly Glu TrpPhe Pro Ser Tyr Gln Val Tyr Cys 290 295 300 Ile Lys Ser Glu Gln Thr TrpPro Ser Thr His Glu Thr Leu Leu Thr 305 310 315 320 Thr Trp Lys Ile ValAla Phe Thr Ala Thr Ser Val Leu Leu Val Leu 325 330 335 Leu Leu Val IleLeu Ala Arg Met Phe Gln Thr Lys Phe Lys Ala His 340 345 350 Phe Pro ProArg Gly Pro Pro Arg Ser Ser Ser Ser Asp Pro Asp Phe 355 360 365 Val ValVal Asp Gly Val Pro Val Met Leu Pro Ser Tyr Asp Glu Ala 370 375 380 ValSer Gly Gly Leu Ser Ala Leu Gly Pro Gly Tyr Met Ala Ser Val 385 390 395400 Gly Gln Gly Cys Pro Leu Pro Val Asp Asp Gln Ser Pro Pro Ala Tyr 405410 415 Pro Gly Ser Gly Asp Thr Asp Thr Gly Pro Gly Glu Ser Glu Thr Cys420 425 430 Asp Ser Val Ser Gly Ser Ser Glu Leu Leu Gln Ser Leu Tyr SerPro 435 440 445 Pro Arg Cys Gln Glu Ser Thr His Pro Ala Ser Asp Asn ProAsp Ile 450 455 460 Ile Ala Ser Thr Ala Glu Glu Val Ala Ser Thr Ser ProGly Ile His 465 470 475 480 His Ala His Trp Val Leu Phe Leu Arg Asn 485490 133 23 DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 133 atctcctatc gctgctttcc cgg 23 134 23DNA Artificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 134 agccaggatc gcagtaaaac tcc 23 135 50 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 135 atttaaactt gatgggtctg cgtatcttga gtgcttacaaaaccttatct 50 136 1815 DNA Homo sapiens 136 cccacgcgtc cgctccgcgccctccccccc gcctcccgtg cggtccgtcg gtggcctaga 60 gatgctgctg ccgcggttgcagttgtcgcg cacgcctctg cccgccagcc cgctccaccg 120 ccgtagcgcc cgagtgtcggggggcgcacc cgagtcgggc catgaggccg ggaaccgcgc 180 tacaggccgt gctgctggccgtgctgctgg tggggctgcg ggccgcgacg ggtcgcctgc 240 tgagtgcctc ggatttggacctcagaggag ggcagccagt ctgccgggga gggacacaga 300 ggccttgtta taaagtcatttacttccatg atacttctcg aagactgaac tttgaggaag 360 ccaaagaagc ctgcaggagggatggaggcc agctagtcag catcgagtct gaagatgaac 420 agaaactgat agaaaagttcattgaaaacc tcttgccatc tgatggtgac ttctggattg 480 ggctcaggag gcgtgaggagaaacaaagca atagcacagc ctgccaggac ctttatgctt 540 ggactgatgg cagcatatcacaatttagga actggtatgt ggatgagccg tcctgcggca 600 gcgaggtctg cgtggtcatgtaccatcagc catcggcacc cgctggcatc ggaggcccct 660 acatgttcca gtggaatgatgaccggtgca acatgaagaa caatttcatt tgcaaatatt 720 ctgatgagaa accagcagttccttctagag aagctgaagg tgaggaaaca gagctgacaa 780 cacctgtact tccagaagaaacacaggaag aagatgccaa aaaaacattt aaagaaagta 840 gagaagctgc cttgaatctggcctacatcc taatccccag cattcccctt ctcctcctcc 900 ttgtggtcac cacagttgtatgttgggttt ggatctgtag aaaaagaaaa cgggagcagc 960 cagaccctag cacaaagaagcaacacacca tctggccctc tcctcaccag ggaaacagcc 1020 cggacctaga ggtctacaatgtcataagaa aacaaagcga agctgactta gctgagaccc 1080 ggccagacct gaagaatatttcattccgag tgtgttcggg agaagccact cccgatgaca 1140 tgtcttgtga ctatgacaacatggctgtga acccatcaga aagtgggttt gtgactctgg 1200 tgagcgtgga gagtggatttgtgaccaatg acatttatga gttctcccca gaccaaatgg 1260 ggaggagtaa ggagtctggatgggtggaaa atgaaatata tggttattag gacatataaa 1320 aaactgaaac tgacaacaatggaaaagaaa tgataagcaa aatcctctta ttttctataa 1380 ggaaaataca cagaaggtctatgaacaagc ttagatcagg tcctgtggat gagcatgtgg 1440 tccccacgac ctcctgttggacccccacgt tttggctgta tcctttatcc cagccagtca 1500 tccagctcga ccttatgagaaggtaccttg cccaggtctg gcacatagta gagtctcaat 1560 aaatgtcact tggttggttgtatctaactt ttaagggaca gagctttacc tggcagtgat 1620 aaagatgggc tgtggagcttggaaaaccac ctctgttttc cttgctctat acagcagcac 1680 atattatcat acagacagaaaatccagaat cttttcaaag cccacatatg gtagcacagg 1740 ttggcctgtg catcggcaattctcatatct gtttttttca aagaataaaa tcaaataaag 1800 agcaggaaaa aaaaa 1815137 382 PRT Homo sapiens 137 Met Arg Pro Gly Thr Ala Leu Gln Ala Val LeuLeu Ala Val Leu Leu 1 5 10 15 Val Gly Leu Arg Ala Ala Thr Gly Arg LeuLeu Ser Ala Ser Asp Leu 20 25 30 Asp Leu Arg Gly Gly Gln Pro Val Cys ArgGly Gly Thr Gln Arg Pro 35 40 45 Cys Tyr Lys Val Ile Tyr Phe His Asp ThrSer Arg Arg Leu Asn Phe 50 55 60 Glu Glu Ala Lys Glu Ala Cys Arg Arg AspGly Gly Gln Leu Val Ser 65 70 75 80 Ile Glu Ser Glu Asp Glu Gln Lys LeuIle Glu Lys Phe Ile Glu Asn 85 90 95 Leu Leu Pro Ser Asp Gly Asp Phe TrpIle Gly Leu Arg Arg Arg Glu 100 105 110 Glu Lys Gln Ser Asn Ser Thr AlaCys Gln Asp Leu Tyr Ala Trp Thr 115 120 125 Asp Gly Ser Ile Ser Gln PheArg Asn Trp Tyr Val Asp Glu Pro Ser 130 135 140 Cys Gly Ser Glu Val CysVal Val Met Tyr His Gln Pro Ser Ala Pro 145 150 155 160 Ala Gly Ile GlyGly Pro Tyr Met Phe Gln Trp Asn Asp Asp Arg Cys 165 170 175 Asn Met LysAsn Asn Phe Ile Cys Lys Tyr Ser Asp Glu Lys Pro Ala 180 185 190 Val ProSer Arg Glu Ala Glu Gly Glu Glu Thr Glu Leu Thr Thr Pro 195 200 205 ValLeu Pro Glu Glu Thr Gln Glu Glu Asp Ala Lys Lys Thr Phe Lys 210 215 220Glu Ser Arg Glu Ala Ala Leu Asn Leu Ala Tyr Ile Leu Ile Pro Ser 225 230235 240 Ile Pro Leu Leu Leu Leu Leu Val Val Thr Thr Val Val Cys Trp Val245 250 255 Trp Ile Cys Arg Lys Arg Lys Arg Glu Gln Pro Asp Pro Ser ThrLys 260 265 270 Lys Gln His Thr Ile Trp Pro Ser Pro His Gln Gly Asn SerPro Asp 275 280 285 Leu Glu Val Tyr Asn Val Ile Arg Lys Gln Ser Glu AlaAsp Leu Ala 290 295 300 Glu Thr Arg Pro Asp Leu Lys Asn Ile Ser Phe ArgVal Cys Ser Gly 305 310 315 320 Glu Ala Thr Pro Asp Asp Met Ser Cys AspTyr Asp Asn Met Ala Val 325 330 335 Asn Pro Ser Glu Ser Gly Phe Val ThrLeu Val Ser Val Glu Ser Gly 340 345 350 Phe Val Thr Asn Asp Ile Tyr GluPhe Ser Pro Asp Gln Met Gly Arg 355 360 365 Ser Lys Glu Ser Gly Trp ValGlu Asn Glu Ile Tyr Gly Tyr 370 375 380 138 50 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe 138gttcattgaa aacctcttgc catctgatgg tgacttctgg attgggctca 50 139 24 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 139 aagccaaaga agcctgcagg aggg 24 140 24 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 140 cagtccaagc ataaaggtcc tggc 24 141 1514 DNAHomo sapiens 141 ggggtctccc tcagggccgg gaggcacagc ggtccctgct tgctgaagggctggatgtac 60 gcatccgcag gttcccgcgg acttgggggc gcccgctgag ccccggcgcccgcagaagac 120 ttgtgtttgc ctcctgcagc ctcaacccgg agggcagcga gggcctaccaccatgatcac 180 tggtgtgttc agcatgcgct tgtggacccc agtgggcgtc ctgacctcgctggcgtactg 240 cctgcaccag cggcgggtgg ccctggccga gctgcaggag gccgatggccagtgtccggt 300 cgaccgcagc ctgctgaagt tgaaaatggt gcaggtcgtg tttcgacacggggctcggag 360 tcctctcaag ccgctcccgc tggaggagca ggtagagtgg aacccccagctattagaggt 420 cccaccccaa actcagtttg attacacagt caccaatcta gctggtggtccgaaaccata 480 ttctccttac gactctcaat accatgagac caccctgaag gggggcatgtttgctgggca 540 gctgaccaag gtgggcatgc agcaaatgtt tgccttggga gagagactgaggaagaacta 600 tgtggaagac attccctttc tttcaccaac cttcaaccca caggaggtctttattcgttc 660 cactaacatt tttcggaatc tggagtccac ccgttgtttg ctggctgggcttttccagtg 720 tcagaaagaa ggacccatca tcatccacac tgatgaagca gattcagaagtcttgtatcc 780 caactaccaa agctgctgga gcctgaggca gagaaccaga ggccggaggcagactgcctc 840 tttacagcca ggaatctcag aggatttgaa aaaggtgaag gacaggatgggcattgacag 900 tagtgataaa gtggacttct tcatcctcct ggacaacgtg gctgccgagcaggcacacaa 960 cctcccaagc tgccccatgc tgaagagatt tgcacggatg atcgaacagagagctgtgga 1020 cacatccttg tacatactgc ccaaggaaga cagggaaagt cttcagatggcagtaggccc 1080 attcctccac atcctagaga gcaacctgct gaaagccatg gactctgccactgcccccga 1140 caagatcaga aagctgtatc tctatgcggc tcatgatgtg accttcataccgctcttaat 1200 gaccctgggg atttttgacc acaaatggcc accgtttgct gttgacctgaccatggaact 1260 ttaccagcac ctggaatcta aggagtggtt tgtgcagctc tattaccacgggaaggagca 1320 ggtgccgaga ggttgccctg atgggctctg cccgctggac atgttcttgaatgccatgtc 1380 agtttatacc ttaagcccag aaaaatacca tgcactctgc tctcaaactcaggtgatgga 1440 agttggaaat gaagagtaac tgatttataa aagcaggatg tgttgattttaaaataaagt 1500 gcctttatac aatg 1514 142 428 PRT Homo sapiens 142 MetIle Thr Gly Val Phe Ser Met Arg Leu Trp Thr Pro Val Gly Val 1 5 10 15Leu Thr Ser Leu Ala Tyr Cys Leu His Gln Arg Arg Val Ala Leu Ala 20 25 30Glu Leu Gln Glu Ala Asp Gly Gln Cys Pro Val Asp Arg Ser Leu Leu 35 40 45Lys Leu Lys Met Val Gln Val Val Phe Arg His Gly Ala Arg Ser Pro 50 55 60Leu Lys Pro Leu Pro Leu Glu Glu Gln Val Glu Trp Asn Pro Gln Leu 65 70 7580 Leu Glu Val Pro Pro Gln Thr Gln Phe Asp Tyr Thr Val Thr Asn Leu 85 9095 Ala Gly Gly Pro Lys Pro Tyr Ser Pro Tyr Asp Ser Gln Tyr His Glu 100105 110 Thr Thr Leu Lys Gly Gly Met Phe Ala Gly Gln Leu Thr Lys Val Gly115 120 125 Met Gln Gln Met Phe Ala Leu Gly Glu Arg Leu Arg Lys Asn TyrVal 130 135 140 Glu Asp Ile Pro Phe Leu Ser Pro Thr Phe Asn Pro Gln GluVal Phe 145 150 155 160 Ile Arg Ser Thr Asn Ile Phe Arg Asn Leu Glu SerThr Arg Cys Leu 165 170 175 Leu Ala Gly Leu Phe Gln Cys Gln Lys Glu GlyPro Ile Ile Ile His 180 185 190 Thr Asp Glu Ala Asp Ser Glu Val Leu TyrPro Asn Tyr Gln Ser Cys 195 200 205 Trp Ser Leu Arg Gln Arg Thr Arg GlyArg Arg Gln Thr Ala Ser Leu 210 215 220 Gln Pro Gly Ile Ser Glu Asp LeuLys Lys Val Lys Asp Arg Met Gly 225 230 235 240 Ile Asp Ser Ser Asp LysVal Asp Phe Phe Ile Leu Leu Asp Asn Val 245 250 255 Ala Ala Glu Gln AlaHis Asn Leu Pro Ser Cys Pro Met Leu Lys Arg 260 265 270 Phe Ala Arg MetIle Glu Gln Arg Ala Val Asp Thr Ser Leu Tyr Ile 275 280 285 Leu Pro LysGlu Asp Arg Glu Ser Leu Gln Met Ala Val Gly Pro Phe 290 295 300 Leu HisIle Leu Glu Ser Asn Leu Leu Lys Ala Met Asp Ser Ala Thr 305 310 315 320Ala Pro Asp Lys Ile Arg Lys Leu Tyr Leu Tyr Ala Ala His Asp Val 325 330335 Thr Phe Ile Pro Leu Leu Met Thr Leu Gly Ile Phe Asp His Lys Trp 340345 350 Pro Pro Phe Ala Val Asp Leu Thr Met Glu Leu Tyr Gln His Leu Glu355 360 365 Ser Lys Glu Trp Phe Val Gln Leu Tyr Tyr His Gly Lys Glu GlnVal 370 375 380 Pro Arg Gly Cys Pro Asp Gly Leu Cys Pro Leu Asp Met PheLeu Asn 385 390 395 400 Ala Met Ser Val Tyr Thr Leu Ser Pro Glu Lys TyrHis Ala Leu Cys 405 410 415 Ser Gln Thr Gln Val Met Glu Val Gly Asn GluGlu 420 425 143 24 DNA Artificial Sequence Description of ArtificialSequence Synthetic oligonucleotide probe 143 ccaactacca aagctgctgg agcc24 144 24 DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 144 gcagctctat taccacggga agga 24 145 24DNA Artificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 145 tccttcccgt ggtaatagag ctgc 24 146 45 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 146 ggcagagaac cagaggccgg aggagactgc ctctttacagccagg 45 147 1686 DNA Homo sapiens 147 ctcctcttaa catacttgca gctaaaactaaatattgctg cttggggacc tccttctagc 60 cttaaatttc agctcatcac cttcacctgccttggtcatg gctctgctat tctccttgat 120 ccttgccatt tgcaccagac ctggattcctagcgtctcca tctggagtgc ggctggtggg 180 gggcctccac cgctgtgaag ggcgggtggaggtggaacag aaaggccagt ggggcaccgt 240 gtgtgatgac ggctgggaca ttaaggacgtggctgtgttg tgccgggagc tgggctgtgg 300 agctgccagc ggaaccccta gtggtattttgtatgagcca ccagcagaaa aagagcaaaa 360 ggtcctcatc caatcagtca gttgcacaggaacagaagat acattggctc agtgtgagca 420 agaagaagtt tatgattgtt cacatgatgaagatgctggg gcatcgtgtg agaacccaga 480 gagctctttc tccccagtcc cagagggtgtcaggctggct gacggccctg ggcattgcaa 540 gggacgcgtg gaagtgaagc accagaaccagtggtatacc gtgtgccaga caggctggag 600 cctccgggcc gcaaaggtgg tgtgccggcagctgggatgt gggagggctg tactgactca 660 aaaacgctgc aacaagcatg cctatggccgaaaacccatc tggctgagcc agatgtcatg 720 ctcaggacga gaagcaaccc ttcaggattgcccttctggg ccttggggga agaacacctg 780 caaccatgat gaagacacgt gggtcgaatgtgaagatccc tttgacttga gactagtagg 840 aggagacaac ctctgctctg ggcgactggaggtgctgcac aagggcgtat ggggctctgt 900 ctgtgatgac aactggggag aaaaggaggaccaggtggta tgcaagcaac tgggctgtgg 960 gaagtccctc tctccctcct tcagagaccggaaatgctat ggccctgggg ttggccgcat 1020 ctggctggat aatgttcgtt gctcaggggaggagcagtcc ctggagcagt gccagcacag 1080 attttggggg tttcacgact gcacccaccaggaagatgtg gctgtcatct gctcagtgta 1140 ggtgggcatc atctaatctg ttgagtgcctgaatagaaga aaaacacaga agaagggagc 1200 atttactgtc tacatgactg catgggatgaacactgatct tcttctgccc ttggactggg 1260 acttatactt ggtgcccctg attctcaggccttcagagtt ggatcagaac ttacaacatc 1320 aggtctagtt ctcaggccat cagacatagtttggaactac atcaccacct ttcctatgtc 1380 tccacattgc acacagcaga ttcccagcctccataattgt gtgtatcaac tacttaaata 1440 cattctcaca cacacacaca cacacacacacacacacaca cacacataca ccatttgtcc 1500 tgtttctctg aagaactctg acaaaatacagattttggta ctgaaagaga ttctagagga 1560 acggaatttt aaggataaat tttctgaattggttatgggg tttctgaaat tggctctata 1620 atctaattag atataaaatt ctggtaactttatttacaat aataaagata gcactatgtg 1680 ttcaaa 1686 148 347 PRT Homosapiens 148 Met Ala Leu Leu Phe Ser Leu Ile Leu Ala Ile Cys Thr Arg ProGly 1 5 10 15 Phe Leu Ala Ser Pro Ser Gly Val Arg Leu Val Gly Gly LeuHis Arg 20 25 30 Cys Glu Gly Arg Val Glu Val Glu Gln Lys Gly Gln Trp GlyThr Val 35 40 45 Cys Asp Asp Gly Trp Asp Ile Lys Asp Val Ala Val Leu CysArg Glu 50 55 60 Leu Gly Cys Gly Ala Ala Ser Gly Thr Pro Ser Gly Ile LeuTyr Glu 65 70 75 80 Pro Pro Ala Glu Lys Glu Gln Lys Val Leu Ile Gln SerVal Ser Cys 85 90 95 Thr Gly Thr Glu Asp Thr Leu Ala Gln Cys Glu Gln GluGlu Val Tyr 100 105 110 Asp Cys Ser His Asp Glu Asp Ala Gly Ala Ser CysGlu Asn Pro Glu 115 120 125 Ser Ser Phe Ser Pro Val Pro Glu Gly Val ArgLeu Ala Asp Gly Pro 130 135 140 Gly His Cys Lys Gly Arg Val Glu Val LysHis Gln Asn Gln Trp Tyr 145 150 155 160 Thr Val Cys Gln Thr Gly Trp SerLeu Arg Ala Ala Lys Val Val Cys 165 170 175 Arg Gln Leu Gly Cys Gly ArgAla Val Leu Thr Gln Lys Arg Cys Asn 180 185 190 Lys His Ala Tyr Gly ArgLys Pro Ile Trp Leu Ser Gln Met Ser Cys 195 200 205 Ser Gly Arg Glu AlaThr Leu Gln Asp Cys Pro Ser Gly Pro Trp Gly 210 215 220 Lys Asn Thr CysAsn His Asp Glu Asp Thr Trp Val Glu Cys Glu Asp 225 230 235 240 Pro PheAsp Leu Arg Leu Val Gly Gly Asp Asn Leu Cys Ser Gly Arg 245 250 255 LeuGlu Val Leu His Lys Gly Val Trp Gly Ser Val Cys Asp Asp Asn 260 265 270Trp Gly Glu Lys Glu Asp Gln Val Val Cys Lys Gln Leu Gly Cys Gly 275 280285 Lys Ser Leu Ser Pro Ser Phe Arg Asp Arg Lys Cys Tyr Gly Pro Gly 290295 300 Val Gly Arg Ile Trp Leu Asp Asn Val Arg Cys Ser Gly Glu Glu Gln305 310 315 320 Ser Leu Glu Gln Cys Gln His Arg Phe Trp Gly Phe His AspCys Thr 325 330 335 His Gln Glu Asp Val Ala Val Ile Cys Ser Val 340 345149 24 DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 149 ttcagctcat caccttcacc tgcc 24 150 24DNA Artificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 150 ggctcataca aaataccact aggg 24 151 50 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 151 gggcctccac cgctgtgaag ggcgggtgga ggtggaacagaaaggccagt 50 152 1427 DNA Homo sapiens 152 actgcactcg gttctatcgattgaattccc cggggatcct ctagagatcc ctcgacctcg 60 acccacgcgt ccgcggacgcgtgggcggac gcgtgggccg gctaccagga agagtctgcc 120 gaaggtgaag gccatggacttcatcacctc cacagccatc ctgcccctgc tgttcggctg 180 cctgggcgtc ttcggcctcttccggctgct gcagtgggtg cgcgggaagg cctacctgcg 240 gaatgctgtg gtggtgatcacaggcgccac ctcagggctg ggcaaagaat gtgcaaaagt 300 cttctatgct gcgggtgctaaactggtgct ctgtggccgg aatggtgggg ccctagaaga 360 gctcatcaga gaacttaccgcttctcatgc caccaaggtg cagacacaca agccttactt 420 ggtgaccttc gacctcacagactctggggc catagttgca gcagcagctg agatcctgca 480 gtgctttggc tatgtcgacatacttgtcaa caatgctggg atcagctacc gtggtaccat 540 catggacacc acagtggatgtggacaagag ggtcatggag acaaactact ttggcccagt 600 tgctctaacg aaagcactcctgccctccat gatcaagagg aggcaaggcc acattgtcgc 660 catcagcagc atccagggcaagatgagcat tccttttcga tcagcatatg cagcctccaa 720 gcacgcaacc caggctttctttgactgtct gcgtgccgag atggaacagt atgaaattga 780 ggtgaccgtc atcagccccggctacatcca caccaacctc tctgtaaatg ccatcaccgc 840 ggatggatct aggtatggagttatggacac caccacagcc cagggccgaa gccctgtgga 900 ggtggcccag gatgttcttgctgctgtggg gaagaagaag aaagatgtga tcctggctga 960 cttactgcct tccttggctgtttatcttcg aactctggct cctgggctct tcttcagcct 1020 catggcctcc agggccagaaaagagcggaa atccaagaac tcctagtact ctgaccagcc 1080 agggccaggg cagagaagcagcactcttag gcttgcttac tctacaaggg acagttgcat 1140 ttgttgagac tttaatggagatttgtctca caagtgggaa agactgaaga aacacatctc 1200 gtgcagatct gctggcagaggacaatcaaa aacgacaaca agcttcttcc cagggtgagg 1260 ggaaacactt aaggaataaatatggagctg gggtttaaca ctaaaaacta gaaataaaca 1320 tctcaaacag taaaaaaaaaaaaaaagggc ggccgcgact ctagagtcga cctgcagaag 1380 cttggccgcc atggcccaacttgtttattg cagcttataa tggttac 1427 153 310 PRT Homo sapiens 153 Met AspPhe Ile Thr Ser Thr Ala Ile Leu Pro Leu Leu Phe Gly Cys 1 5 10 15 LeuGly Val Phe Gly Leu Phe Arg Leu Leu Gln Trp Val Arg Gly Lys 20 25 30 AlaTyr Leu Arg Asn Ala Val Val Val Ile Thr Gly Ala Thr Ser Gly 35 40 45 LeuGly Lys Glu Cys Ala Lys Val Phe Tyr Ala Ala Gly Ala Lys Leu 50 55 60 ValLeu Cys Gly Arg Asn Gly Gly Ala Leu Glu Glu Leu Ile Arg Glu 65 70 75 80Leu Thr Ala Ser His Ala Thr Lys Val Gln Thr His Lys Pro Tyr Leu 85 90 95Val Thr Phe Asp Leu Thr Asp Ser Gly Ala Ile Val Ala Ala Ala Ala 100 105110 Glu Ile Leu Gln Cys Phe Gly Tyr Val Asp Ile Leu Val Asn Asn Ala 115120 125 Gly Ile Ser Tyr Arg Gly Thr Ile Met Asp Thr Thr Val Asp Val Asp130 135 140 Lys Arg Val Met Glu Thr Asn Tyr Phe Gly Pro Val Ala Leu ThrLys 145 150 155 160 Ala Leu Leu Pro Ser Met Ile Lys Arg Arg Gln Gly HisIle Val Ala 165 170 175 Ile Ser Ser Ile Gln Gly Lys Met Ser Ile Pro PheArg Ser Ala Tyr 180 185 190 Ala Ala Ser Lys His Ala Thr Gln Ala Phe PheAsp Cys Leu Arg Ala 195 200 205 Glu Met Glu Gln Tyr Glu Ile Glu Val ThrVal Ile Ser Pro Gly Tyr 210 215 220 Ile His Thr Asn Leu Ser Val Asn AlaIle Thr Ala Asp Gly Ser Arg 225 230 235 240 Tyr Gly Val Met Asp Thr ThrThr Ala Gln Gly Arg Ser Pro Val Glu 245 250 255 Val Ala Gln Asp Val LeuAla Ala Val Gly Lys Lys Lys Lys Asp Val 260 265 270 Ile Leu Ala Asp LeuLeu Pro Ser Leu Ala Val Tyr Leu Arg Thr Leu 275 280 285 Ala Pro Gly LeuPhe Phe Ser Leu Met Ala Ser Arg Ala Arg Lys Glu 290 295 300 Arg Lys SerLys Asn Ser 305 310 154 24 DNA Artificial Sequence Description ofArtificial Sequence Synthetic oligonucleotide probe 154 ggtgctaaactggtgctctg tggc 24 155 20 DNA Artificial Sequence Description ofArtificial Sequence Synthetic oligonucleotide probe 155 cagggcaagatgagcattcc 20 156 24 DNA Artificial Sequence Description of ArtificialSequence Synthetic oligonucleotide probe 156 tcatactgtt ccatctcggc acgc24 157 50 DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 157 aatggtgggg ccctagaaga gctcatcagagaactcaccg cttctcatgc 50 158 1771 DNA Homo sapiens 158 cccacgcgtccgctggtgtt agatcgagca accctctaaa agcagtttag agtggtaaaa 60 aaaaaaaaaaacacaccaaa cgctcgcagc cacaaaaggg atgaaatttc ttctggacat 120 cctcctgcttctcccgttac tgatcgtctg ctccctagag tccttcgtga agctttttat 180 tcctaagaggagaaaatcag tcaccggcga aatcgtgctg attacaggag ctgggcatgg 240 aattgggagactgactgcct atgaatttgc taaacttaaa agcaagctgg ttctctggga 300 tataaataagcatggactgg aggaaacagc tgccaaatgc aagggactgg gtgccaaggt 360 tcatacctttgtggtagact gcagcaaccg agaagatatt tacagctctg caaagaaggt 420 gaaggcagaaattggagatg ttagtatttt agtaaataat gctggtgtag tctatacatc 480 agatttgtttgctacacaag atcctcagat tgaaaagact tttgaagtta atgtacttgc 540 acatttctggactacaaagg catttcttcc tgcaatgacg aagaataacc atggccatat 600 tgtcactgtggcttcggcag ctggacatgt ctcggtcccc ttcttactgg cttactgttc 660 aagcaagtttgctgctgttg gatttcataa aactttgaca gatgaactgg ctgccttaca 720 aataactggagtcaaaacaa catgtctgtg tcctaatttc gtaaacactg gcttcatcaa 780 aaatccaagtacaagtttgg gacccactct ggaacctgag gaagtggtaa acaggctgat 840 gcatgggattctgactgagc agaagatgat ttttattcca tcttctatag cttttttaac 900 aacattggaaaggatccttc ctgagcgttt cctggcagtt ttaaaacgaa aaatcagtgt 960 taagtttgatgcagttattg gatataaaat gaaagcgcaa taagcaccta gttttctgaa 1020 aactgatttaccaggtttag gttgatgtca tctaatagtg ccagaatttt aatgtttgaa 1080 cttctgttttttctaattat ccccatttct tcaatatcat ttttgaggct ttggcagtct 1140 tcatttactaccacttgttc tttagccaaa agctgattac atatgatata aacagagaaa 1200 tacctttagaggtgacttta aggaaaatga agaaaaagaa ccaaaatgac tttattaaaa 1260 taatttccaagattatttgt ggctcacctg aaggctttgc aaaatttgta ccataaccgt 1320 ttatttaacatatattttta tttttgattg cacttaaatt ttgtataatt tgtgtttctt 1380 tttctgttctacataaaatc agaaacttca agctctctaa ataaaatgaa ggactatatc 1440 tagtggtatttcacaatgaa tatcatgaac tctcaatggg taggtttcat cctacccatt 1500 gccactctgtttcctgagag atacctcaca ttccaatgcc aaacatttct gcacagggaa 1560 gctagaggtggatacacgtg ttgcaagtat aaaagcatca ctgggattta aggagaattg 1620 agagaatgtacccacaaatg gcagcaataa taaatggatc acacttaaaa aaaaaaaaaa 1680 aaaaaaaaaaaaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1740 aaaaaaaaaaaaaaaaaaaa aaaaaaaaaa a 1771 159 300 PRT Homo sapiens 159 Met Lys PheLeu Leu Asp Ile Leu Leu Leu Leu Pro Leu Leu Ile Val 1 5 10 15 Cys SerLeu Glu Ser Phe Val Lys Leu Phe Ile Pro Lys Arg Arg Lys 20 25 30 Ser ValThr Gly Glu Ile Val Leu Ile Thr Gly Ala Gly His Gly Ile 35 40 45 Gly ArgLeu Thr Ala Tyr Glu Phe Ala Lys Leu Lys Ser Lys Leu Val 50 55 60 Leu TrpAsp Ile Asn Lys His Gly Leu Glu Glu Thr Ala Ala Lys Cys 65 70 75 80 LysGly Leu Gly Ala Lys Val His Thr Phe Val Val Asp Cys Ser Asn 85 90 95 ArgGlu Asp Ile Tyr Ser Ser Ala Lys Lys Val Lys Ala Glu Ile Gly 100 105 110Asp Val Ser Ile Leu Val Asn Asn Ala Gly Val Val Tyr Thr Ser Asp 115 120125 Leu Phe Ala Thr Gln Asp Pro Gln Ile Glu Lys Thr Phe Glu Val Asn 130135 140 Val Leu Ala His Phe Trp Thr Thr Lys Ala Phe Leu Pro Ala Met Thr145 150 155 160 Lys Asn Asn His Gly His Ile Val Thr Val Ala Ser Ala AlaGly His 165 170 175 Val Ser Val Pro Phe Leu Leu Ala Tyr Cys Ser Ser LysPhe Ala Ala 180 185 190 Val Gly Phe His Lys Thr Leu Thr Asp Glu Leu AlaAla Leu Gln Ile 195 200 205 Thr Gly Val Lys Thr Thr Cys Leu Cys Pro AsnPhe Val Asn Thr Gly 210 215 220 Phe Ile Lys Asn Pro Ser Thr Ser Leu GlyPro Thr Leu Glu Pro Glu 225 230 235 240 Glu Val Val Asn Arg Leu Met HisGly Ile Leu Thr Glu Gln Lys Met 245 250 255 Ile Phe Ile Pro Ser Ser IleAla Phe Leu Thr Thr Leu Glu Arg Ile 260 265 270 Leu Pro Glu Arg Phe LeuAla Val Leu Lys Arg Lys Ile Ser Val Lys 275 280 285 Phe Asp Ala Val IleGly Tyr Lys Met Lys Ala Gln 290 295 300 160 23 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe 160ggtgaaggca gaaattggag atg 23 161 24 DNA Artificial Sequence Descriptionof Artificial Sequence Synthetic oligonucleotide probe 161 atcccatgcatcagcctgtt tacc 24 162 48 DNA Artificial Sequence Description ofArtificial Sequence Synthetic oligonucleotide probe 162 gctggtgtagtctatacatc agatttgttt gctacacaag atcctcag 48 163 2076 DNA Homo sapiens163 cccacgcgtc cgcggacgcg tgggtcgact agttctagat cgcgagcggc cgcccgcggc 60tcagggagga gcaccgactg cgccgcaccc tgagagatgg ttggtgccat gtggaaggtg 120attgtttcgc tggtcctgtt gatgcctggc ccctgtgatg ggctgtttcg ctccctatac 180agaagtgttt ccatgccacc taagggagac tcaggacagc cattatttct caccccttac 240attgaagctg ggaagatcca aaaaggaaga gaattgagtt tggtcggccc tttcccagga 300ctgaacatga agagttatgc cggcttcctc accgtgaata agacttacaa cagcaacctc 360ttcttctggt tcttcccagc tcagatacag ccagaagatg ccccagtagt tctctggcta 420cagggtgggc cgggaggttc atccatgttt ggactctttg tggaacatgg gccttatgtt 480gtcacaagta acatgacctt gcgtgacaga gacttcccct ggaccacaac gctctccatg 540ctttacattg acaatccagt gggcacaggc ttcagtttta ctgatgatac ccacggatat 600gcagtcaatg aggacgatgt agcacgggat ttatacagtg cactaattca gtttttccag 660atatttcctg aatataaaaa taatgacttt tatgtcactg gggagtctta tgcagggaaa 720tatgtgccag ccattgcaca cctcatccat tccctcaacc ctgtgagaga ggtgaagatc 780aacctgaacg gaattgctat tggagatgga tattctgatc ccgaatcaat tatagggggc 840tatgcagaat tcctgtacca aattggcttg ttggatgaga agcaaaaaaa gtacttccag 900aagcagtgcc atgaatgcat agaacacatc aggaagcaga actggtttga ggcctttgaa 960atactggata aactactaga tggcgactta acaagtgatc cttcttactt ccagaatgtt 1020acaggatgta gtaattacta taactttttg cggtgcacgg aacctgagga tcagctttac 1080tatgtgaaat ttttgtcact cccagaggtg agacaagcca tccacgtggg gaatcagact 1140tttaatgatg gaactatagt tgaaaagtac ttgcgagaag atacagtaca gtcagttaag 1200ccatggttaa ctgaaatcat gaataattat aaggttctga tctacaatgg ccaactggac 1260atcatcgtgg cagctgccct gacagagcgc tccttgatgg gcatggactg gaaaggatcc 1320caggaataca agaaggcaga aaaaaaagtt tggaagatct ttaaatctga cagtgaagtg 1380gctggttaca tccggcaagc gggtgacttc catcaggtaa ttattcgagg tggaggacat 1440attttaccct atgaccagcc tctgagagct tttgacatga ttaatcgatt catttatgga 1500aaaggatggg atccttatgt tggataaact accttcccaa aagagaacat cagaggtttt 1560cattgctgaa aagaaaatcg taaaaacaga aaatgtcata ggaataaaaa aattatcttt 1620tcatatctgc aagatttttt tcatcaataa aaattatcct tgaaacaagt gagcttttgt 1680ttttgggggg agatgtttac tacaaaatta acatgagtac atgagtaaga attacattat 1740ttaacttaaa ggatgaaagg tatggatgat gtgacactga gacaagatgt ataaatgaaa 1800ttttagggtc ttgaatagga agttttaatt tcttctaaga gtaagtgaaa agtgcagttg 1860taacaaacaa agctgtaaca tctttttctg ccaataacag aagtttggca tgccgtgaag 1920gtgtttggaa atattattgg ataagaatag ctcaattatc ccaaataaat ggatgaagct 1980ataatagttt tggggaaaag attctcaaat gtataaagtc ttagaacaaa agaattcttt 2040gaaataaaaa tattatatat aaaagtaaaa aaaaaa 2076 164 476 PRT Homo sapiens164 Met Val Gly Ala Met Trp Lys Val Ile Val Ser Leu Val Leu Leu Met 1 510 15 Pro Gly Pro Cys Asp Gly Leu Phe Arg Ser Leu Tyr Arg Ser Val Ser 2025 30 Met Pro Pro Lys Gly Asp Ser Gly Gln Pro Leu Phe Leu Thr Pro Tyr 3540 45 Ile Glu Ala Gly Lys Ile Gln Lys Gly Arg Glu Leu Ser Leu Val Gly 5055 60 Pro Phe Pro Gly Leu Asn Met Lys Ser Tyr Ala Gly Phe Leu Thr Val 6570 75 80 Asn Lys Thr Tyr Asn Ser Asn Leu Phe Phe Trp Phe Phe Pro Ala Gln85 90 95 Ile Gln Pro Glu Asp Ala Pro Val Val Leu Trp Leu Gln Gly Gly Pro100 105 110 Gly Gly Ser Ser Met Phe Gly Leu Phe Val Glu His Gly Pro TyrVal 115 120 125 Val Thr Ser Asn Met Thr Leu Arg Asp Arg Asp Phe Pro TrpThr Thr 130 135 140 Thr Leu Ser Met Leu Tyr Ile Asp Asn Pro Val Gly ThrGly Phe Ser 145 150 155 160 Phe Thr Asp Asp Thr His Gly Tyr Ala Val AsnGlu Asp Asp Val Ala 165 170 175 Arg Asp Leu Tyr Ser Ala Leu Ile Gln PhePhe Gln Ile Phe Pro Glu 180 185 190 Tyr Lys Asn Asn Asp Phe Tyr Val ThrGly Glu Ser Tyr Ala Gly Lys 195 200 205 Tyr Val Pro Ala Ile Ala His LeuIle His Ser Leu Asn Pro Val Arg 210 215 220 Glu Val Lys Ile Asn Leu AsnGly Ile Ala Ile Gly Asp Gly Tyr Ser 225 230 235 240 Asp Pro Glu Ser IleIle Gly Gly Tyr Ala Glu Phe Leu Tyr Gln Ile 245 250 255 Gly Leu Leu AspGlu Lys Gln Lys Lys Tyr Phe Gln Lys Gln Cys His 260 265 270 Glu Cys IleGlu His Ile Arg Lys Gln Asn Trp Phe Glu Ala Phe Glu 275 280 285 Ile LeuAsp Lys Leu Leu Asp Gly Asp Leu Thr Ser Asp Pro Ser Tyr 290 295 300 PheGln Asn Val Thr Gly Cys Ser Asn Tyr Tyr Asn Phe Leu Arg Cys 305 310 315320 Thr Glu Pro Glu Asp Gln Leu Tyr Tyr Val Lys Phe Leu Ser Leu Pro 325330 335 Glu Val Arg Gln Ala Ile His Val Gly Asn Gln Thr Phe Asn Asp Gly340 345 350 Thr Ile Val Glu Lys Tyr Leu Arg Glu Asp Thr Val Gln Ser ValLys 355 360 365 Pro Trp Leu Thr Glu Ile Met Asn Asn Tyr Lys Val Leu IleTyr Asn 370 375 380 Gly Gln Leu Asp Ile Ile Val Ala Ala Ala Leu Thr GluArg Ser Leu 385 390 395 400 Met Gly Met Asp Trp Lys Gly Ser Gln Glu TyrLys Lys Ala Glu Lys 405 410 415 Lys Val Trp Lys Ile Phe Lys Ser Asp SerGlu Val Ala Gly Tyr Ile 420 425 430 Arg Gln Ala Gly Asp Phe His Gln ValIle Ile Arg Gly Gly Gly His 435 440 445 Ile Leu Pro Tyr Asp Gln Pro LeuArg Ala Phe Asp Met Ile Asn Arg 450 455 460 Phe Ile Tyr Gly Lys Gly TrpAsp Pro Tyr Val Gly 465 470 475 165 24 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe 165ttccatgcca cctaagggag actc 24 166 24 DNA Artificial Sequence Descriptionof Artificial Sequence Synthetic oligonucleotide probe 166 tggatgaggtgtgcaatggc tggc 24 167 24 DNA Artificial Sequence Description ofArtificial Sequence Synthetic oligonucleotide probe 167 agctctcagaggctggtcat aggg 24 168 50 DNA Artificial Sequence Description ofArtificial Sequence Synthetic oligonucleotide probe 168 gtcggccctttcccaggact gaacatgaag agttatgccg gcttcctcac 50 169 2477 DNA Homo sapiens169 cgagggcttt tccggctccg gaatggcaca tgtgggaatc ccagtcttgt tggctacaac 60atttttccct ttcctaacaa gttctaacag ctgttctaac agctagtgat caggggttct 120tcttgctgga gaagaaaggg ctgagggcag agcagggcac tctcactcag ggtgaccagc 180tccttgcctc tctgtggata acagagcatg agaaagtgaa gagatgcagc ggagtgaggt 240gatggaagtc taaaatagga aggaattttg tgtgcaatat cagactctgg gagcagttga 300cctggagagc ctgggggagg gcctgcctaa caagctttca aaaaacagga gcgacttcca 360ctgggctggg ataagacgtg ccggtaggat agggaagact gggtttagtc ctaatatcaa 420attgactggc tgggtgaact tcaacagcct tttaacctct ctgggagatg aaaacgatgg 480cttaaggggc cagaaataga gatgctttgt aaaataaaat tttaaaaaaa gcaagtattt 540tatagcataa aggctagaga ccaaaataga taacaggatt ccctgaacat tcctaagagg 600gagaaagtat gttaaaaata gaaaaaccaa aatgcagaag gaggagactc acagagctaa 660accaggatgg ggaccctggg tcaggccagc ctctttgctc ctcccggaaa ttatttttgg 720tctgaccact ctgccttgtg ttttgcagaa tcatgtgagg gccaaccggg gaaggtggag 780cagatgagca cacacaggag ccgtctcctc accgccgccc ctctcagcat ggaacagagg 840cagccctggc cccgggccct ggaggtggac agccgctctg tggtcctgct ctcagtggtc 900tgggtgctgc tggccccccc agcagccggc atgcctcagt tcagcacctt ccactctgag 960aatcgtgact ggaccttcaa ccacttgacc gtccaccaag ggacgggggc cgtctatgtg 1020ggggccatca accgggtcta taagctgaca ggcaacctga ccatccaggt ggctcataag 1080acagggccag aagaggacaa caagtctcgt tacccgcccc tcatcgtgca gccctgcagc 1140gaagtgctca ccctcaccaa caatgtcaac aagctgctca tcattgacta ctctgagaac 1200cgcctgctgg cctgtgggag cctctaccag ggggtctgca agctgctgcg gctggatgac 1260ctcttcatcc tggtggagcc atcccacaag aaggagcact acctgtccag tgtcaacaag 1320acgggcacca tgtacggggt gattgtgcgc tctgagggtg aggatggcaa gctcttcatc 1380ggcacggctg tggatgggaa gcaggattac ttcccgaccc tgtccagccg gaagctgccc 1440cgagaccctg agtcctcagc catgctcgac tatgagctac acagcgattt tgtctcctct 1500ctcatcaaga tcccttcaga caccctggcc ctggtctccc actttgacat cttctacatc 1560tacggctttg ctagtggggg ctttgtctac tttctcactg tccagcccga gacccctgag 1620ggtgtggcca tcaactccgc tggagacctc ttctacacct cacgcatcgt gcggctctgc 1680aaggatgacc ccaagttcca ctcatacgtg tccctgccct tcggctgcac ccgggccggg 1740gtggaatacc gcctcctgca ggctgcttac ctggccaagc ctggggactc actggcccag 1800gccttcaata tcaccagcca ggacgatgta ctctttgcca tcttctccaa agggcagaag 1860cagtatcacc acccgcccga tgactctgcc ctgtgtgcct tccctatccg ggccatcaac 1920ttgcagatca aggagcgcct gcagtcctgc taccagggcg agggcaacct ggagctcaac 1980tggctgctgg ggaaggacgt ccagtgcacg aaggcgcctg tccccatcga tgataacttc 2040tgtggactgg acatcaacca gcccctggga ggctcaactc cagtggaggg cctgaccctg 2100tacaccacca gcagggaccg catgacctct gtggcctcct acgtttacaa cggctacagc 2160gtggtttttg tggggactaa gagtggcaag ctgaaaaagg taagagtcta tgagttcaga 2220tgctccaatg ccattcacct cctcagcaaa gagtccctct tggaaggtag ctattggtgg 2280agatttaact ataggcaact ttattttctt ggggaacaaa ggtgaaatgg ggaggtaaga 2340aggggttaat tttgtgactt agcttctagc tacttcctcc agccatcagt cattgggtat 2400gtaaggaatg caagcgtatt tcaatatttc ccaaacttta agaaaaaact ttaagaaggt 2460acatctgcaa aagcaaa 2477 170 552 PRT Homo sapiens 170 Met Gly Thr Leu GlyGln Ala Ser Leu Phe Ala Pro Pro Gly Asn Tyr 1 5 10 15 Phe Trp Ser AspHis Ser Ala Leu Cys Phe Ala Glu Ser Cys Glu Gly 20 25 30 Gln Pro Gly LysVal Glu Gln Met Ser Thr His Arg Ser Arg Leu Leu 35 40 45 Thr Ala Ala ProLeu Ser Met Glu Gln Arg Gln Pro Trp Pro Arg Ala 50 55 60 Leu Glu Val AspSer Arg Ser Val Val Leu Leu Ser Val Val Trp Val 65 70 75 80 Leu Leu AlaPro Pro Ala Ala Gly Met Pro Gln Phe Ser Thr Phe His 85 90 95 Ser Glu AsnArg Asp Trp Thr Phe Asn His Leu Thr Val His Gln Gly 100 105 110 Thr GlyAla Val Tyr Val Gly Ala Ile Asn Arg Val Tyr Lys Leu Thr 115 120 125 GlyAsn Leu Thr Ile Gln Val Ala His Lys Thr Gly Pro Glu Glu Asp 130 135 140Asn Lys Ser Arg Tyr Pro Pro Leu Ile Val Gln Pro Cys Ser Glu Val 145 150155 160 Leu Thr Leu Thr Asn Asn Val Asn Lys Leu Leu Ile Ile Asp Tyr Ser165 170 175 Glu Asn Arg Leu Leu Ala Cys Gly Ser Leu Tyr Gln Gly Val CysLys 180 185 190 Leu Leu Arg Leu Asp Asp Leu Phe Ile Leu Val Glu Pro SerHis Lys 195 200 205 Lys Glu His Tyr Leu Ser Ser Val Asn Lys Thr Gly ThrMet Tyr Gly 210 215 220 Val Ile Val Arg Ser Glu Gly Glu Asp Gly Lys LeuPhe Ile Gly Thr 225 230 235 240 Ala Val Asp Gly Lys Gln Asp Tyr Phe ProThr Leu Ser Ser Arg Lys 245 250 255 Leu Pro Arg Asp Pro Glu Ser Ser AlaMet Leu Asp Tyr Glu Leu His 260 265 270 Ser Asp Phe Val Ser Ser Leu IleLys Ile Pro Ser Asp Thr Leu Ala 275 280 285 Leu Val Ser His Phe Asp IlePhe Tyr Ile Tyr Gly Phe Ala Ser Gly 290 295 300 Gly Phe Val Tyr Phe LeuThr Val Gln Pro Glu Thr Pro Glu Gly Val 305 310 315 320 Ala Ile Asn SerAla Gly Asp Leu Phe Tyr Thr Ser Arg Ile Val Arg 325 330 335 Leu Cys LysAsp Asp Pro Lys Phe His Ser Tyr Val Ser Leu Pro Phe 340 345 350 Gly CysThr Arg Ala Gly Val Glu Tyr Arg Leu Leu Gln Ala Ala Tyr 355 360 365 LeuAla Lys Pro Gly Asp Ser Leu Ala Gln Ala Phe Asn Ile Thr Ser 370 375 380Gln Asp Asp Val Leu Phe Ala Ile Phe Ser Lys Gly Gln Lys Gln Tyr 385 390395 400 His His Pro Pro Asp Asp Ser Ala Leu Cys Ala Phe Pro Ile Arg Ala405 410 415 Ile Asn Leu Gln Ile Lys Glu Arg Leu Gln Ser Cys Tyr Gln GlyGlu 420 425 430 Gly Asn Leu Glu Leu Asn Trp Leu Leu Gly Lys Asp Val GlnCys Thr 435 440 445 Lys Ala Pro Val Pro Ile Asp Asp Asn Phe Cys Gly LeuAsp Ile Asn 450 455 460 Gln Pro Leu Gly Gly Ser Thr Pro Val Glu Gly LeuThr Leu Tyr Thr 465 470 475 480 Thr Ser Arg Asp Arg Met Thr Ser Val AlaSer Tyr Val Tyr Asn Gly 485 490 495 Tyr Ser Val Val Phe Val Gly Thr LysSer Gly Lys Leu Lys Lys Val 500 505 510 Arg Val Tyr Glu Phe Arg Cys SerAsn Ala Ile His Leu Leu Ser Lys 515 520 525 Glu Ser Leu Leu Glu Gly SerTyr Trp Trp Arg Phe Asn Tyr Arg Gln 530 535 540 Leu Tyr Phe Leu Gly GluGln Arg 545 550 171 20 DNA Artificial Sequence Description of ArtificialSequence Synthetic oligonucleotide probe 171 tggaataccg cctcctgcag 20172 24 DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 172 cttctgccct ttggagaaga tggc 24 173 43DNA Artificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 173 ggactcactg gcccaggcct tcaatatcac cagccaggacgat 42 174 3106 DNA Homo sapiens modified_base (1683) a, t, c or g 174aggctcccgc gcgcggctga gtgcggactg gagtgggaac ccgggtcccc gcgcttagag 60aacacgcgat gaccacgtgg agcctccggc ggaggccggc ccgcacgctg ggactcctgc 120tgctggtcgt cttgggcttc ctggtgctcc gcaggctgga ctggagcacc ctggtccctc 180tgcggctccg ccatcgacag ctggggctgc aggccaaggg ctggaacttc atgctggagg 240attccacctt ctggatcttc gggggctcca tccactattt ccgtgtgccc agggagtact 300ggagggaccg cctgctgaag atgaaggcct gtggcttgaa caccctcacc acctatgttc 360cgtggaacct gcatgagcca gaaagaggca aatttgactt ctctgggaac ctggacctgg 420aggccttcgt cctgatggcc gcagagatcg ggctgtgggt gattctgcgt ccaggcccct 480acatctgcag tgagatggac ctcgggggct tgcccagctg gctactccaa gaccctggca 540tgaggctgag gacaacttac aagggcttca ccgaagcagt ggacctttat tttgaccacc 600tgatgtccag ggtggtgcca ctccagtaca agcgtggggg acctatcatt gccgtgcagg 660tggagaatga atatggttcc tataataaag accccgcata catgccctac gtcaagaagg 720cactggagga ccgtggcatt gtggaactgc tcctgacttc agacaacaag gatgggctga 780gcaaggggat tgtccaggga gtcttggcca ccatcaactt gcagtcaaca cacgagctgc 840agctactgac cacctttctc ttcaacgtcc aggggactca gcccaagatg gtgatggagt 900actggacggg gtggtttgac tcgtggggag gccctcacaa tatcttggat tcttctgagg 960ttttgaaaac cgtgtctgcc attgtggacg ccggctcctc catcaacctc tacatgttcc 1020acggaggcac caactttggc ttcatgaatg gagccatgca cttccatgac tacaagtcag 1080atgtcaccag ctatgactat gatgctgtgc tgacagaagc cggcgattac acggccaagt 1140acatgaagct tcgagacttc ttcggctcca tctcaggcat ccctctccct cccccacctg 1200accttcttcc caagatgccg tatgagccct taacgccagt cttgtacctg tctctgtggg 1260acgccctcaa gtacctgggg gagccaatca agtctgaaaa gcccatcaac atggagaacc 1320tgccagtcaa tgggggaaat ggacagtcct tcgggtacat tctctatgag accagcatca 1380cctcgtctgg catcctcagt ggccacgtgc atgatcgggg gcaggtgttt gtgaacacag 1440tatccatagg attcttggac tacaagacaa cgaagattgc tgtccccctg atccagggtt 1500acaccgtgct gaggatcttg gtggagaatc gtgggcgagt caactatggg gagaatattg 1560atgaccagcg caaaggctta attggaaatc tctatctgaa tgattcaccc ctgaaaaact 1620tcagaatcta tagcctggat atgaagaaga gcttctttca gaggttcggc ctggacaaat 1680ggngttccct cccagaaaca cccacattac ctgctttctt cttgggtagc ttgtccatca 1740gctccacgcc ttgtgacacc tttctgaagc tggagggctg ggagaagggg gttgtattca 1800tcaatggcca gaaccttgga cgttactgga acattggacc ccagaagacg ctttacctcc 1860caggtccctg gttgagcagc ggaatcaacc aggtcatcgt ttttgaggag acgatggcgg 1920gccctgcatt acagttcacg gaaacccccc acctgggcag gaaccagtac attaagtgag 1980cggtggcacc ccctcctgct ggtgccagtg ggagactgcc gcctcctctt gacctgaagc 2040ctggtggctg ctgccccacc cctcactgca aaagcatctc cttaagtagc aacctcaggg 2100actgggggct acagtctgcc cctgtctcag ctcaaaaccc taagcctgca gggaaaggtg 2160ggatggctct gggcctggct ttgttgatga tggctttcct acagccctgc tcttgtgccg 2220aggctgtcgg gctgtctcta gggtgggagc agctaatcag atcgcccagc ctttggccct 2280cagaaaaagt gctgaaacgt gcccttgcac cggacgtcac agccctgcga gcatctgctg 2340gactcaggcg tgctctttgc tggttcctgg gaggcttggc cacatccctc atggccccat 2400tttatccccg aaatcctggg tgtgtcacca gtgtagaggg tggggaaggg gtgtctcacc 2460tgagctgact ttgttcttcc ttcacaacct tctgagcctt ctttgggatt ctggaaggaa 2520ctcggcgtga gaaacatgtg acttcccctt tcccttccca ctcgctgctt cccacagggt 2580gacaggctgg gctggagaaa cagaaatcct caccctgcgt cttcccaagt tagcaggtgt 2640ctctggtgtt cagtgaggag gacatgtgag tcctggcaga agccatggcc catgtctgca 2700catccaggga ggaggacaga aggcccagct cacatgtgag tcctggcaga agccatggcc 2760catgtctgca catccaggga ggaggacaga aggcccagct cacatgtgag tcctggcaga 2820agccatggcc catgtctgca catccaggga ggaggacaga aggcccagct cacatgtgag 2880tcctggcaga agccatggcc catgtctgca catccaggga ggaggacaga aggcccagct 2940cagtggcccc cgctccccac cccccacgcc cgaacagcag gggcagagca gccctccttc 3000gaagtgtgtc caagtccgca tttgagcctt gttctggggc ccagcccaac acctggcttg 3060ggctcactgt cctgagttgc agtaaagcta taaccttgaa tcacaa 3106 175 636 PRT Homosapiens MOD_RES (539) Any amino acid 175 Met Thr Thr Trp Ser Leu Arg ArgArg Pro Ala Arg Thr Leu Gly Leu 1 5 10 15 Leu Leu Leu Val Val Leu GlyPhe Leu Val Leu Arg Arg Leu Asp Trp 20 25 30 Ser Thr Leu Val Pro Leu ArgLeu Arg His Arg Gln Leu Gly Leu Gln 35 40 45 Ala Lys Gly Trp Asn Phe MetLeu Glu Asp Ser Thr Phe Trp Ile Phe 50 55 60 Gly Gly Ser Ile His Tyr PheArg Val Pro Arg Glu Tyr Trp Arg Asp 65 70 75 80 Arg Leu Leu Lys Met LysAla Cys Gly Leu Asn Thr Leu Thr Thr Tyr 85 90 95 Val Pro Trp Asn Leu HisGlu Pro Glu Arg Gly Lys Phe Asp Phe Ser 100 105 110 Gly Asn Leu Asp LeuGlu Ala Phe Val Leu Met Ala Ala Glu Ile Gly 115 120 125 Leu Trp Val IleLeu Arg Pro Gly Pro Tyr Ile Cys Ser Glu Met Asp 130 135 140 Leu Gly GlyLeu Pro Ser Trp Leu Leu Gln Asp Pro Gly Met Arg Leu 145 150 155 160 ArgThr Thr Tyr Lys Gly Phe Thr Glu Ala Val Asp Leu Tyr Phe Asp 165 170 175His Leu Met Ser Arg Val Val Pro Leu Gln Tyr Lys Arg Gly Gly Pro 180 185190 Ile Ile Ala Val Gln Val Glu Asn Glu Tyr Gly Ser Tyr Asn Lys Asp 195200 205 Pro Ala Tyr Met Pro Tyr Val Lys Lys Ala Leu Glu Asp Arg Gly Ile210 215 220 Val Glu Leu Leu Leu Thr Ser Asp Asn Lys Asp Gly Leu Ser LysGly 225 230 235 240 Ile Val Gln Gly Val Leu Ala Thr Ile Asn Leu Gln SerThr His Glu 245 250 255 Leu Gln Leu Leu Thr Thr Phe Leu Phe Asn Val GlnGly Thr Gln Pro 260 265 270 Lys Met Val Met Glu Tyr Trp Thr Gly Trp PheAsp Ser Trp Gly Gly 275 280 285 Pro His Asn Ile Leu Asp Ser Ser Glu ValLeu Lys Thr Val Ser Ala 290 295 300 Ile Val Asp Ala Gly Ser Ser Ile AsnLeu Tyr Met Phe His Gly Gly 305 310 315 320 Thr Asn Phe Gly Phe Met AsnGly Ala Met His Phe His Asp Tyr Lys 325 330 335 Ser Asp Val Thr Ser TyrAsp Tyr Asp Ala Val Leu Thr Glu Ala Gly 340 345 350 Asp Tyr Thr Ala LysTyr Met Lys Leu Arg Asp Phe Phe Gly Ser Ile 355 360 365 Ser Gly Ile ProLeu Pro Pro Pro Pro Asp Leu Leu Pro Lys Met Pro 370 375 380 Tyr Glu ProLeu Thr Pro Val Leu Tyr Leu Ser Leu Trp Asp Ala Leu 385 390 395 400 LysTyr Leu Gly Glu Pro Ile Lys Ser Glu Lys Pro Ile Asn Met Glu 405 410 415Asn Leu Pro Val Asn Gly Gly Asn Gly Gln Ser Phe Gly Tyr Ile Leu 420 425430 Tyr Glu Thr Ser Ile Thr Ser Ser Gly Ile Leu Ser Gly His Val His 435440 445 Asp Arg Gly Gln Val Phe Val Asn Thr Val Ser Ile Gly Phe Leu Asp450 455 460 Tyr Lys Thr Thr Lys Ile Ala Val Pro Leu Ile Gln Gly Tyr ThrVal 465 470 475 480 Leu Arg Ile Leu Val Glu Asn Arg Gly Arg Val Asn TyrGly Glu Asn 485 490 495 Ile Asp Asp Gln Arg Lys Gly Leu Ile Gly Asn LeuTyr Leu Asn Asp 500 505 510 Ser Pro Leu Lys Asn Phe Arg Ile Tyr Ser LeuAsp Met Lys Lys Ser 515 520 525 Phe Phe Gln Arg Phe Gly Leu Asp Lys TrpXaa Ser Leu Pro Glu Thr 530 535 540 Pro Thr Leu Pro Ala Phe Phe Leu GlySer Leu Ser Ile Ser Ser Thr 545 550 555 560 Pro Cys Asp Thr Phe Leu LysLeu Glu Gly Trp Glu Lys Gly Val Val 565 570 575 Phe Ile Asn Gly Gln AsnLeu Gly Arg Tyr Trp Asn Ile Gly Pro Gln 580 585 590 Lys Thr Leu Tyr LeuPro Gly Pro Trp Leu Ser Ser Gly Ile Asn Gln 595 600 605 Val Ile Val PheGlu Glu Thr Met Ala Gly Pro Ala Leu Gln Phe Thr 610 615 620 Glu Thr ProHis Leu Gly Arg Asn Gln Tyr Ile Lys 625 630 635 176 2505 DNA Homosapiens 176 ggggacgcgg agctgagagg ctccgggcta gctaggtgta ggggtggacgggtcccagga 60 ccctggtgag ggttctctac ttggccttcg gtgggggtca agacgcaggcacctacgcca 120 aaggggagca aagccgggct cggcccgagg cccccaggac ctccatctcccaatgttgga 180 ggaatccgac acgtgacggt ctgtccgccg tctcagacta gaggagcgctgtaaacgcca 240 tggctcccaa gaagctgtcc tgccttcgtt ccctgctgct gccgctcagcctgacgctac 300 tgctgcccca ggcagacact cggtcgttcg tagtggatag gggtcatgaccggtttctcc 360 tagacggggc cccgttccgc tatgtgtctg gcagcctgca ctactttcgggtaccgcggg 420 tgctttgggc cgaccggctt ttgaagatgc gatggagcgg cctcaacgccatacagtttt 480 atgtgccctg gaactaccac gagccacagc ctggggtcta taactttaatggcagccggg 540 acctcattgc ctttctgaat gaggcagctc tagcgaacct gttggtcatactgagaccag 600 gaccttacat ctgtgcagag tgggagatgg ggggtctccc atcctggttgcttcgaaaac 660 ctgaaattca tctaagaacc tcagatccag acttccttgc cgcagtggactcctggttca 720 aggtcttgct gcccaagata tatccatggc tttatcacaa tgggggcaacatcattagca 780 ttcaggtgga gaatgaatat ggtagctaca gagcctgtga cttcagctacatgaggcact 840 tggctgggct cttccgtgca ctgctaggag aaaagatctt gctcttcaccacagatgggc 900 ctgaaggact caagtgtggc tccctccggg gactctatac cactgtagattttggcccag 960 ctgacaacat gaccaaaatc tttaccctgc ttcggaagta tgaaccccatgggccattgg 1020 taaactctga gtactacaca ggctggctgg attactgggg ccagaatcactccacacggt 1080 ctgtgtcagc tgtaaccaaa ggactagaga acatgctcaa gttgggagccagtgtgaaca 1140 tgtacatgtt ccatggaggt accaactttg gatattggaa tggtgccgataagaagggac 1200 gcttccttcc gattactacc agctatgact atgatgcacc tatatctgaagcaggggacc 1260 ccacacctaa gctttttgct cttcgagatg tcatcagcaa gttccaggaagttcctttgg 1320 gacctttacc tcccccgagc cccaagatga tgcttggacc tgtgactctgcacctggttg 1380 ggcatttact ggctttccta gacttgcttt gcccccgtgg gcccattcattcaatcttgc 1440 caatgacctt tgaggctgtc aagcaggacc atggcttcat gttgtaccgaacctatatga 1500 cccataccat ttttgagcca acaccattct gggtgccaaa taatggagtccatgaccgtg 1560 cctatgtgat ggtggatggg gtgttccagg gtgttgtgga gcgaaatatgagagacaaac 1620 tatttttgac ggggaaactg gggtccaaac tggatatctt ggtggagaacatggggaggc 1680 tcagctttgg gtctaacagc agtgacttca agggcctgtt gaagccaccaattctggggc 1740 aaacaatcct tacccagtgg atgatgttcc ctctgaaaat tgataaccttgtgaagtggt 1800 ggtttcccct ccagttgcca aaatggccat atcctcaagc tccttctggccccacattct 1860 actccaaaac atttccaatt ttaggctcag ttggggacac atttctatatctacctggat 1920 ggaccaaggg ccaagtctgg atcaatgggt ttaacttggg ccggtactggacaaagcagg 1980 ggccacaaca gaccctctac gtgccaagat tcctgctgtt tcctaggggagccctcaaca 2040 aaattacatt gctggaacta gaagatgtac ctctccagcc ccaagtccaatttttggata 2100 agcctatcct caatagcact agtactttgc acaggacaca tatcaattccctttcagctg 2160 atacactgag tgcctctgaa ccaatggagt taagtgggca ctgaaaggtaggccgggcat 2220 ggtggctcat gcctgtaatc ccagcacttt gggaggctga gacgggtggattacctgagg 2280 tcaggacttc aagaccagcc tggccaacat ggtgaaaccc cgtctccactaaaaatacaa 2340 aaattagccg ggcgtgatgg tgggcacctc taatcccagc tacttgggaggctgagggca 2400 ggagaattgc ttgaatccag gaggcagagg ttgcagtgag tggaggttgtaccactgcac 2460 tccagcctgg ctgacagtga gacactccat ctcaaaaaaa aaaaa 2505177 654 PRT Homo sapiens 177 Met Ala Pro Lys Lys Leu Ser Cys Leu Arg SerLeu Leu Leu Pro Leu 1 5 10 15 Ser Leu Thr Leu Leu Leu Pro Gln Ala AspThr Arg Ser Phe Val Val 20 25 30 Asp Arg Gly His Asp Arg Phe Leu Leu AspGly Ala Pro Phe Arg Tyr 35 40 45 Val Ser Gly Ser Leu His Tyr Phe Arg ValPro Arg Val Leu Trp Ala 50 55 60 Asp Arg Leu Leu Lys Met Arg Trp Ser GlyLeu Asn Ala Ile Gln Phe 65 70 75 80 Tyr Val Pro Trp Asn Tyr His Glu ProGln Pro Gly Val Tyr Asn Phe 85 90 95 Asn Gly Ser Arg Asp Leu Ile Ala PheLeu Asn Glu Ala Ala Leu Ala 100 105 110 Asn Leu Leu Val Ile Leu Arg ProGly Pro Tyr Ile Cys Ala Glu Trp 115 120 125 Glu Met Gly Gly Leu Pro SerTrp Leu Leu Arg Lys Pro Glu Ile His 130 135 140 Leu Arg Thr Ser Asp ProAsp Phe Leu Ala Ala Val Asp Ser Trp Phe 145 150 155 160 Lys Val Leu LeuPro Lys Ile Tyr Pro Trp Leu Tyr His Asn Gly Gly 165 170 175 Asn Ile IleSer Ile Gln Val Glu Asn Glu Tyr Gly Ser Tyr Arg Ala 180 185 190 Cys AspPhe Ser Tyr Met Arg His Leu Ala Gly Leu Phe Arg Ala Leu 195 200 205 LeuGly Glu Lys Ile Leu Leu Phe Thr Thr Asp Gly Pro Glu Gly Leu 210 215 220Lys Cys Gly Ser Leu Arg Gly Leu Tyr Thr Thr Val Asp Phe Gly Pro 225 230235 240 Ala Asp Asn Met Thr Lys Ile Phe Thr Leu Leu Arg Lys Tyr Glu Pro245 250 255 His Gly Pro Leu Val Asn Ser Glu Tyr Tyr Thr Gly Trp Leu AspTyr 260 265 270 Trp Gly Gln Asn His Ser Thr Arg Ser Val Ser Ala Val ThrLys Gly 275 280 285 Leu Glu Asn Met Leu Lys Leu Gly Ala Ser Val Asn MetTyr Met Phe 290 295 300 His Gly Gly Thr Asn Phe Gly Tyr Trp Asn Gly AlaAsp Lys Lys Gly 305 310 315 320 Arg Phe Leu Pro Ile Thr Thr Ser Tyr AspTyr Asp Ala Pro Ile Ser 325 330 335 Glu Ala Gly Asp Pro Thr Pro Lys LeuPhe Ala Leu Arg Asp Val Ile 340 345 350 Ser Lys Phe Gln Glu Val Pro LeuGly Pro Leu Pro Pro Pro Ser Pro 355 360 365 Lys Met Met Leu Gly Pro ValThr Leu His Leu Val Gly His Leu Leu 370 375 380 Ala Phe Leu Asp Leu LeuCys Pro Arg Gly Pro Ile His Ser Ile Leu 385 390 395 400 Pro Met Thr PheGlu Ala Val Lys Gln Asp His Gly Phe Met Leu Tyr 405 410 415 Arg Thr TyrMet Thr His Thr Ile Phe Glu Pro Thr Pro Phe Trp Val 420 425 430 Pro AsnAsn Gly Val His Asp Arg Ala Tyr Val Met Val Asp Gly Val 435 440 445 PheGln Gly Val Val Glu Arg Asn Met Arg Asp Lys Leu Phe Leu Thr 450 455 460Gly Lys Leu Gly Ser Lys Leu Asp Ile Leu Val Glu Asn Met Gly Arg 465 470475 480 Leu Ser Phe Gly Ser Asn Ser Ser Asp Phe Lys Gly Leu Leu Lys Pro485 490 495 Pro Ile Leu Gly Gln Thr Ile Leu Thr Gln Trp Met Met Phe ProLeu 500 505 510 Lys Ile Asp Asn Leu Val Lys Trp Trp Phe Pro Leu Gln LeuPro Lys 515 520 525 Trp Pro Tyr Pro Gln Ala Pro Ser Gly Pro Thr Phe TyrSer Lys Thr 530 535 540 Phe Pro Ile Leu Gly Ser Val Gly Asp Thr Phe LeuTyr Leu Pro Gly 545 550 555 560 Trp Thr Lys Gly Gln Val Trp Ile Asn GlyPhe Asn Leu Gly Arg Tyr 565 570 575 Trp Thr Lys Gln Gly Pro Gln Gln ThrLeu Tyr Val Pro Arg Phe Leu 580 585 590 Leu Phe Pro Arg Gly Ala Leu AsnLys Ile Thr Leu Leu Glu Leu Glu 595 600 605 Asp Val Pro Leu Gln Pro GlnVal Gln Phe Leu Asp Lys Pro Ile Leu 610 615 620 Asn Ser Thr Ser Thr LeuHis Arg Thr His Ile Asn Ser Leu Ser Ala 625 630 635 640 Asp Thr Leu SerAla Ser Glu Pro Met Glu Leu Ser Gly His 645 650 178 24 DNA ArtificialSequence Description of Artificial Sequence Synthetic oligonucleotideprobe 178 tggctactcc aagaccctgg catg 24 179 24 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe 179tggacaaatc cccttgctca gccc 24 180 50 DNA Artificial Sequence Descriptionof Artificial Sequence Synthetic oligonucleotide probe 180 gggcttcaccgaagcagtgg acctttattt tgaccacctg atgtccaggg 50 181 22 DNA ArtificialSequence Description of Artificial Sequence Synthetic oligonucleotideprobe 181 ccagctatga ctatgatgca cc 22 182 24 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe 182tggcacccag aatggtgttg gctc 24 183 50 DNA Artificial Sequence Descriptionof Artificial Sequence Synthetic oligonucleotide probe 183 cgagatgtcatcagcaagtt ccaggaagtt cctttgggac ctttacctcc 50 184 1947 DNA Homo sapiens184 gctttgaaca cgtctgcaag cccaaagttg agcatctgat tggttatgag gtatttgagt 60gcacccacaa tatggcttac atgttgaaaa agcttctcat cagttacata tccattattt 120gtgtttatgg ctttatctgc ctctacactc tcttctggtt attcaggata cctttgaagg 180aatattcttt cgaaaaagtc agagaagaga gcagttttag tgacattcca gatgtcaaaa 240acgattttgc gttccttctt cacatggtag accagtatga ccagctatat tccaagcgtt 300ttggtgtgtt cttgtcagaa gttagtgaaa ataaacttag ggaaattagt ttgaaccatg 360agtggacatt tgaaaaactc aggcagcaca tttcacgcaa cgcccaggac aagcaggagt 420tgcatctgtt catgctgtcg ggggtgcccg atgctgtctt tgacctcaca gacctggatg 480tgctaaagct tgaactaatt ccagaagcta aaattcctgc taagatttct caaatgacta 540acctccaaga gctccacctc tgccactgcc ctgcaaaagt tgaacagact gcttttagct 600ttcttcgcga tcacttgaga tgccttcacg tgaagttcac tgatgtggct gaaattcctg 660cctgggtgta tttgctcaaa aaccttcgag agttgtactt aataggcaat ttgaactctg 720aaaacaataa gatgatagga cttgaatctc tccgagagtt gcggcacctt aagattctcc 780acgtgaagag caatttgacc aaagttccct ccaacattac agatgtggct ccacatctta 840caaagttagt cattcataat gacggcacta aactcttggt actgaacagc cttaagaaaa 900tgatgaatgt cgctgagctg gaactccaga actgtgagct agagagaatc ccacatgcta 960ttttcagcct ctctaattta caggaactgg atttaaagtc caataacatt cgcacaattg 1020aggaaatcat cagtttccag catttaaaac gactgacttg tttaaaatta tggcataaca 1080aaattgttac tattcctccc tctattaccc atgtcaaaaa cttggagtca ctttatttct 1140ctaacaacaa gctcgaatcc ttaccagtgg cagtatttag tttacagaaa ctcagatgct 1200tagatgtgag ctacaacaac atttcaatga ttccaataga aataggattg cttcagaacc 1260tgcagcattt gcatatcact gggaacaaag tggacattct gccaaaacaa ttgtttaaat 1320gcataaagtt gaggactttg aatctgggac agaactgcat cacctcactc ccagagaaag 1380ttggtcagct ctcccagctc actcagctgg agctgaaggg gaactgcttg gaccgcctgc 1440cagcccagct gggccagtgt cggatgctca agaaaagcgg gcttgttgtg gaagatcacc 1500tttttgatac cctgccactc gaagtcaaag aggcattgaa tcaagacata aatattccct 1560ttgcaaatgg gatttaaact aagataatat atgcacagtg atgtgcagga acaacttcct 1620agattgcaag tgctcacgta caagttatta caagataatg cattttagga gtagatacat 1680cttttaaaat aaaacagaga ggatgcatag aaggctgata gaagacataa ctgaatgttc 1740aatgtttgta gggttttaag tcattcattt ccaaatcatt tttttttttc ttttggggaa 1800agggaaggaa aaattataat cactaatctt ggttcttttt aaattgtttg taacttggat 1860gctgccgcta ctgaatgttt acaaattgct tgcctgctaa agtaaatgat taaattgaca 1920ttttcttact aaaaaaaaaa aaaaaaa 1947 185 501 PRT Homo sapiens 185 Met AlaTyr Met Leu Lys Lys Leu Leu Ile Ser Tyr Ile Ser Ile Ile 1 5 10 15 CysVal Tyr Gly Phe Ile Cys Leu Tyr Thr Leu Phe Trp Leu Phe Arg 20 25 30 IlePro Leu Lys Glu Tyr Ser Phe Glu Lys Val Arg Glu Glu Ser Ser 35 40 45 PheSer Asp Ile Pro Asp Val Lys Asn Asp Phe Ala Phe Leu Leu His 50 55 60 MetVal Asp Gln Tyr Asp Gln Leu Tyr Ser Lys Arg Phe Gly Val Phe 65 70 75 80Leu Ser Glu Val Ser Glu Asn Lys Leu Arg Glu Ile Ser Leu Asn His 85 90 95Glu Trp Thr Phe Glu Lys Leu Arg Gln His Ile Ser Arg Asn Ala Gln 100 105110 Asp Lys Gln Glu Leu His Leu Phe Met Leu Ser Gly Val Pro Asp Ala 115120 125 Val Phe Asp Leu Thr Asp Leu Asp Val Leu Lys Leu Glu Leu Ile Pro130 135 140 Glu Ala Lys Ile Pro Ala Lys Ile Ser Gln Met Thr Asn Leu GlnGlu 145 150 155 160 Leu His Leu Cys His Cys Pro Ala Lys Val Glu Gln ThrAla Phe Ser 165 170 175 Phe Leu Arg Asp His Leu Arg Cys Leu His Val LysPhe Thr Asp Val 180 185 190 Ala Glu Ile Pro Ala Trp Val Tyr Leu Leu LysAsn Leu Arg Glu Leu 195 200 205 Tyr Leu Ile Gly Asn Leu Asn Ser Glu AsnAsn Lys Met Ile Gly Leu 210 215 220 Glu Ser Leu Arg Glu Leu Arg His LeuLys Ile Leu His Val Lys Ser 225 230 235 240 Asn Leu Thr Lys Val Pro SerAsn Ile Thr Asp Val Ala Pro His Leu 245 250 255 Thr Lys Leu Val Ile HisAsn Asp Gly Thr Lys Leu Leu Val Leu Asn 260 265 270 Ser Leu Lys Lys MetMet Asn Val Ala Glu Leu Glu Leu Gln Asn Cys 275 280 285 Glu Leu Glu ArgIle Pro His Ala Ile Phe Ser Leu Ser Asn Leu Gln 290 295 300 Glu Leu AspLeu Lys Ser Asn Asn Ile Arg Thr Ile Glu Glu Ile Ile 305 310 315 320 SerPhe Gln His Leu Lys Arg Leu Thr Cys Leu Lys Leu Trp His Asn 325 330 335Lys Ile Val Thr Ile Pro Pro Ser Ile Thr His Val Lys Asn Leu Glu 340 345350 Ser Leu Tyr Phe Ser Asn Asn Lys Leu Glu Ser Leu Pro Val Ala Val 355360 365 Phe Ser Leu Gln Lys Leu Arg Cys Leu Asp Val Ser Tyr Asn Asn Ile370 375 380 Ser Met Ile Pro Ile Glu Ile Gly Leu Leu Gln Asn Leu Gln HisLeu 385 390 395 400 His Ile Thr Gly Asn Lys Val Asp Ile Leu Pro Lys GlnLeu Phe Lys 405 410 415 Cys Ile Lys Leu Arg Thr Leu Asn Leu Gly Gln AsnCys Ile Thr Ser 420 425 430 Leu Pro Glu Lys Val Gly Gln Leu Ser Gln LeuThr Gln Leu Glu Leu 435 440 445 Lys Gly Asn Cys Leu Asp Arg Leu Pro AlaGln Leu Gly Gln Cys Arg 450 455 460 Met Leu Lys Lys Ser Gly Leu Val ValGlu Asp His Leu Phe Asp Thr 465 470 475 480 Leu Pro Leu Glu Val Lys GluAla Leu Asn Gln Asp Ile Asn Ile Pro 485 490 495 Phe Ala Asn Gly Ile 500186 21 DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 186 cctccctcta ttacccatgt c 21 187 24DNA Artificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 187 gaccaacttt ctctgggagt gagg 24 188 47 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 188 gtcactttat ttctctaaca acaagctcga atccttaccagtggcag 47 189 2917 DNA Homo sapiens 189 cccacgcgtc cggccttctctctggacttt gcatttccat tccttttcat tgacaaactg 60 acttttttta tttctttttttccatctctg ggccagcttg ggatcctagg ccgccctggg 120 aagacatttg tgttttacacacataaggat ctgtgtttgg ggtttcttct tcctcccctg 180 acattggcat tgcttagtggttgtgtgggg agggagacca cgtgggctca gtgcttgctt 240 gcacttatct gcctaggtacatcgaagtct tttgacctcc atacagtgat tatgcctgtc 300 atcgctggtg gtatcctggcggccttgctc ctgctgatag ttgtcgtgct ctgtctttac 360 ttcaaaatac acaacgcgctaaaagctgca aaggaacctg aagctgtggc tgtaaaaaat 420 cacaacccag acaaggtgtggtgggccaag aacagccagg ccaaaaccat tgccacggag 480 tcttgtcctg ccctgcagtgctgtgaagga tatagaatgt gtgccagttt tgattccctg 540 ccaccttgct gttgcgacataaatgagggc ctctgagtta ggaaaggctc ccttctcaaa 600 gcagagccct gaagacttcaatgatgtcaa tgaggccacc tgtttgtgat gtgcaggcac 660 agaagaaagg cacagctccccatcagtttc atggaaaata actcagtgcc tgctgggaac 720 cagctgctgg agatccctacagagagcttc cactgggggc aacccttcca ggaaggagtt 780 ggggagagag aaccctcactgtggggaatg ctgataaacc agtcacacag ctgctctatt 840 ctcacacaaa tctaccccttgcgtggctgg aactgacgtt tccctggagg tgtccagaaa 900 gctgatgtaa cacagagcctataaaagctg tcggtcctta aggctgccca gcgccttgcc 960 aaaatggagc ttgtaagaaggctcatgcca ttgaccctct taattctctc ctgtttggcg 1020 gagctgacaa tggcggaggctgaaggcaat gcaagctgca cagtcagtct agggggtgcc 1080 aatatggcag agacccacaaagccatgatc ctgcaactca atcccagtga gaactgcacc 1140 tggacaatag aaagaccagaaaacaaaagc atcagaatta tcttttccta tgtccagctt 1200 gatccagatg gaagctgtgaaagtgaaaac attaaagtct ttgacggaac ctccagcaat 1260 gggcctctgc tagggcaagtctgcagtaaa aacgactatg ttcctgtatt tgaatcatca 1320 tccagtacat tgacgtttcaaatagttact gactcagcaa gaattcaaag aactgtcttt 1380 gtcttctact acttcttctctcctaacatc tctattccaa actgtggcgg ttacctggat 1440 accttggaag gatccttcaccagccccaat tacccaaagc cgcatcctga gctggcttat 1500 tgtgtgtggc acatacaagtggagaaagat tacaagataa aactaaactt caaagagatt 1560 ttcctagaaa tagacaaacagtgcaaattt gattttcttg ccatctatga tggcccctcc 1620 accaactctg gcctgattggacaagtctgt ggccgtgtga ctcccacctt cgaatcgtca 1680 tcaaactctc tgactgtcgtgttgtctaca gattatgcca attcttaccg gggattttct 1740 gcttcctaca cctcaatttatgcagaaaac atcaacacta catctttaac ttgctcttct 1800 gacaggatga gagttattataagcaaatcc tacctagagg cttttaactc taatgggaat 1860 aacttgcaac taaaagacccaacttgcaga ccaaaattat caaatgttgt ggaattttct 1920 gtccctctta atggatgtggtacaatcaga aaggtagaag atcagtcaat tacttacacc 1980 aatataatca ccttttctgcatcctcaact tctgaagtga tcacccgtca gaaacaactc 2040 cagattattg tgaagtgtgaaatgggacat aattctacag tggagataat atacataaca 2100 gaagatgatg taatacaaagtcaaaatgca ctgggcaaat ataacaccag catggctctt 2160 tttgaatcca attcatttgaaaagactata cttgaatcac catattatgt ggatttgaac 2220 caaactcttt ttgttcaagttagtctgcac acctcagatc caaatttggt ggtgtttctt 2280 gatacctgta gagcctctcccacctctgac tttgcatctc caacctacga cctaatcaag 2340 agtggatgta gtcgagatgaaacttgtaag gtgtatccct tatttggaca ctatgggaga 2400 ttccagttta atgcctttaaattcttgaga agtatgagct ctgtgtatct gcagtgtaaa 2460 gttttgatat gtgatagcagtgaccaccag tctcgctgca atcaaggttg tgtctccaga 2520 agcaaacgag acatttcttcatataaatgg aaaacagatt ccatcatagg acccattcgt 2580 ctgaaaaggg atcgaagtgcaagtggcaat tcaggatttc agcatgaaac acatgcggaa 2640 gaaactccaa accagcctttcaacagtgtg catctgtttt ccttcatggt tctagctctg 2700 aatgtggtga ctgtagcgacaatcacagtg aggcattttg taaatcaacg ggcagactac 2760 aaataccaga agctgcagaactattaacta acaggtccaa ccctaagtga gacatgtttc 2820 tccaggatgc caaaggaaatgctacctcgt ggctacacat attatgaata aatgaggaag 2880 ggcctgaaag tgacacacaggcctgcatgt aaaaaaa 2917 190 607 PRT Homo sapiens 190 Met Glu Leu Val ArgArg Leu Met Pro Leu Thr Leu Leu Ile Leu Ser 1 5 10 15 Cys Leu Ala GluLeu Thr Met Ala Glu Ala Glu Gly Asn Ala Ser Cys 20 25 30 Thr Val Ser LeuGly Gly Ala Asn Met Ala Glu Thr His Lys Ala Met 35 40 45 Ile Leu Gln LeuAsn Pro Ser Glu Asn Cys Thr Trp Thr Ile Glu Arg 50 55 60 Pro Glu Asn LysSer Ile Arg Ile Ile Phe Ser Tyr Val Gln Leu Asp 65 70 75 80 Pro Asp GlySer Cys Glu Ser Glu Asn Ile Lys Val Phe Asp Gly Thr 85 90 95 Ser Ser AsnGly Pro Leu Leu Gly Gln Val Cys Ser Lys Asn Asp Tyr 100 105 110 Val ProVal Phe Glu Ser Ser Ser Ser Thr Leu Thr Phe Gln Ile Val 115 120 125 ThrAsp Ser Ala Arg Ile Gln Arg Thr Val Phe Val Phe Tyr Tyr Phe 130 135 140Phe Ser Pro Asn Ile Ser Ile Pro Asn Cys Gly Gly Tyr Leu Asp Thr 145 150155 160 Leu Glu Gly Ser Phe Thr Ser Pro Asn Tyr Pro Lys Pro His Pro Glu165 170 175 Leu Ala Tyr Cys Val Trp His Ile Gln Val Glu Lys Asp Tyr LysIle 180 185 190 Lys Leu Asn Phe Lys Glu Ile Phe Leu Glu Ile Asp Lys GlnCys Lys 195 200 205 Phe Asp Phe Leu Ala Ile Tyr Asp Gly Pro Ser Thr AsnSer Gly Leu 210 215 220 Ile Gly Gln Val Cys Gly Arg Val Thr Pro Thr PheGlu Ser Ser Ser 225 230 235 240 Asn Ser Leu Thr Val Val Leu Ser Thr AspTyr Ala Asn Ser Tyr Arg 245 250 255 Gly Phe Ser Ala Ser Tyr Thr Ser IleTyr Ala Glu Asn Ile Asn Thr 260 265 270 Thr Ser Leu Thr Cys Ser Ser AspArg Met Arg Val Ile Ile Ser Lys 275 280 285 Ser Tyr Leu Glu Ala Phe AsnSer Asn Gly Asn Asn Leu Gln Leu Lys 290 295 300 Asp Pro Thr Cys Arg ProLys Leu Ser Asn Val Val Glu Phe Ser Val 305 310 315 320 Pro Leu Asn GlyCys Gly Thr Ile Arg Lys Val Glu Asp Gln Ser Ile 325 330 335 Thr Tyr ThrAsn Ile Ile Thr Phe Ser Ala Ser Ser Thr Ser Glu Val 340 345 350 Ile ThrArg Gln Lys Gln Leu Gln Ile Ile Val Lys Cys Glu Met Gly 355 360 365 HisAsn Ser Thr Val Glu Ile Ile Tyr Ile Thr Glu Asp Asp Val Ile 370 375 380Gln Ser Gln Asn Ala Leu Gly Lys Tyr Asn Thr Ser Met Ala Leu Phe 385 390395 400 Glu Ser Asn Ser Phe Glu Lys Thr Ile Leu Glu Ser Pro Tyr Tyr Val405 410 415 Asp Leu Asn Gln Thr Leu Phe Val Gln Val Ser Leu His Thr SerAsp 420 425 430 Pro Asn Leu Val Val Phe Leu Asp Thr Cys Arg Ala Ser ProThr Ser 435 440 445 Asp Phe Ala Ser Pro Thr Tyr Asp Leu Ile Lys Ser GlyCys Ser Arg 450 455 460 Asp Glu Thr Cys Lys Val Tyr Pro Leu Phe Gly HisTyr Gly Arg Phe 465 470 475 480 Gln Phe Asn Ala Phe Lys Phe Leu Arg SerMet Ser Ser Val Tyr Leu 485 490 495 Gln Cys Lys Val Leu Ile Cys Asp SerSer Asp His Gln Ser Arg Cys 500 505 510 Asn Gln Gly Cys Val Ser Arg SerLys Arg Asp Ile Ser Ser Tyr Lys 515 520 525 Trp Lys Thr Asp Ser Ile IleGly Pro Ile Arg Leu Lys Arg Asp Arg 530 535 540 Ser Ala Ser Gly Asn SerGly Phe Gln His Glu Thr His Ala Glu Glu 545 550 555 560 Thr Pro Asn GlnPro Phe Asn Ser Val His Leu Phe Ser Phe Met Val 565 570 575 Leu Ala LeuAsn Val Val Thr Val Ala Thr Ile Thr Val Arg His Phe 580 585 590 Val AsnGln Arg Ala Asp Tyr Lys Tyr Gln Lys Leu Gln Asn Tyr 595 600 605 191 21DNA Artificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 191 tctctattcc aaactgtggc g 21 192 22 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 192 tttgatgacg attcgaaggt gg 22 193 47 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 193 ggaaggatcc ttcaccagcc ccaattaccc aaagccgcatcctgagc 47 194 2362 DNA Homo sapiens 194 gacggaagaa cagcgctcccgaggccgcgg gagcctgcag agaggacagc cggcctgcgc 60 cgggacatgc ggccccaggagctccccagg ctcgcgttcc cgttgctgct gttgctgttg 120 ctgctgctgc cgccgccgccgtgccctgcc cacagcgcca cgcgcttcga ccccacctgg 180 gagtccctgg acgcccgccagctgcccgcg tggtttgacc aggccaagtt cggcatcttc 240 atccactggg gagtgttttccgtgcccagc ttcggtagcg agtggttctg gtggtattgg 300 caaaaggaaa agataccgaagtatgtggaa tttatgaaag ataattaccc tcctagtttc 360 aaatatgaag attttggaccactatttaca gcaaaatttt ttaatgccaa ccagtgggca 420 gatatttttc aggcctctggtgccaaatac attgtcttaa cttccaaaca tcatgaaggc 480 tttaccttgt gggggtcagaatattcgtgg aactggaatg ccatagatga ggggcccaag 540 agggacattg tcaaggaacttgaggtagcc attaggaaca gaactgacct gcgttttgga 600 ctgtactatt ccctttttgaatggtttcat ccgctcttcc ttgaggatga atccagttca 660 ttccataagc ggcaatttccagtttctaag acattgccag agctctatga gttagtgaac 720 aactatcagc ctgaggttctgtggtcggat ggtgacggag gagcaccgga tcaatactgg 780 aacagcacag gcttcttggcctggttatat aatgaaagcc cagttcgggg cacagtagtc 840 accaatgatc gttggggagctggtagcatc tgtaagcatg gtggcttcta tacctgcagt 900 gatcgttata acccaggacatcttttgcca cataaatggg aaaactgcat gacaatagac 960 aaactgtcct ggggctataggagggaagct ggaatctctg actatcttac aattgaagaa 1020 ttggtgaagc aacttgtagagacagtttca tgtggaggaa atcttttgat gaatattggg 1080 cccacactag atggcaccatttctgtagtt tttgaggagc gactgaggca agtggggtcc 1140 tggctaaaag tcaatggagaagctatttat gaaacctata cctggcgatc ccagaatgac 1200 actgtcaccc cagatgtgtggtacacatcc aagcctaaag aaaaattagt ctatgccatt 1260 tttcttaaat ggcccacatcaggacagctg ttccttggcc atcccaaagc tattctgggg 1320 gcaacagagg tgaaactactgggccatgga cagccactta actggatttc tttggagcaa 1380 aatggcatta tggtagaactgccacagcta accattcatc agatgccgtg taaatggggc 1440 tgggctctag ccctaactaatgtgatctaa agtgcagcag agtggctgat gctgcaagtt 1500 atgtctaagg ctaggaactatcaggtgtct ataattgtag cacatggaga aagcaatgta 1560 aactggataa gaaaattatttggcagttca gccctttccc tttttcccac taaatttttc 1620 ttaaattacc catgtaaccattttaactct ccagtgcact ttgccattaa agtctcttca 1680 cattgatttg tttccatgtgtgactcagag gtgagaattt tttcacatta tagtagcaag 1740 gaattggtgg tattatggaccgaactgaaa attttatgtt gaagccatat cccccatgat 1800 tatatagtta tgcatcacttaatatgggga tattttctgg gaaatgcatt gctagtcaat 1860 ttttttttgt gccaacatcatagagtgtat ttacaaaatc ctagatggca tagcctacta 1920 cacacctaat gtgtatggtatagactgttg ctcctaggct acagacatat acagcatgtt 1980 actgaatact gtaggcaatagtaacagtgg tatttgtata tcgaaacata tggaaacata 2040 gagaaggtac agtaaaaatactgtaaaata aatggtgcac ctgtataggg cacttaccac 2100 gaatggagct tacaggactggaagttgctc tgggtgagtc agtgagtgaa tgtgaaggcc 2160 taggacatta ttgaacactgccagacgtta taaatactgt atgcttaggc tacactacat 2220 ttataaaaaa aagtttttctttcttcaatt ataaattaac ataagtgtac tgtaacttta 2280 caaacgtttt aatttttaaaacctttttgg ctcttttgta ataacactta gcttaaaaca 2340 taaactcatt gtgcaaatgtaa 2362 195 467 PRT Homo sapiens 195 Met Arg Pro Gln Glu Leu Pro Arg LeuAla Phe Pro Leu Leu Leu Leu 1 5 10 15 Leu Leu Leu Leu Leu Pro Pro ProPro Cys Pro Ala His Ser Ala Thr 20 25 30 Arg Phe Asp Pro Thr Trp Glu SerLeu Asp Ala Arg Gln Leu Pro Ala 35 40 45 Trp Phe Asp Gln Ala Lys Phe GlyIle Phe Ile His Trp Gly Val Phe 50 55 60 Ser Val Pro Ser Phe Gly Ser GluTrp Phe Trp Trp Tyr Trp Gln Lys 65 70 75 80 Glu Lys Ile Pro Lys Tyr ValGlu Phe Met Lys Asp Asn Tyr Pro Pro 85 90 95 Ser Phe Lys Tyr Glu Asp PheGly Pro Leu Phe Thr Ala Lys Phe Phe 100 105 110 Asn Ala Asn Gln Trp AlaAsp Ile Phe Gln Ala Ser Gly Ala Lys Tyr 115 120 125 Ile Val Leu Thr SerLys His His Glu Gly Phe Thr Leu Trp Gly Ser 130 135 140 Glu Tyr Ser TrpAsn Trp Asn Ala Ile Asp Glu Gly Pro Lys Arg Asp 145 150 155 160 Ile ValLys Glu Leu Glu Val Ala Ile Arg Asn Arg Thr Asp Leu Arg 165 170 175 PheGly Leu Tyr Tyr Ser Leu Phe Glu Trp Phe His Pro Leu Phe Leu 180 185 190Glu Asp Glu Ser Ser Ser Phe His Lys Arg Gln Phe Pro Val Ser Lys 195 200205 Thr Leu Pro Glu Leu Tyr Glu Leu Val Asn Asn Tyr Gln Pro Glu Val 210215 220 Leu Trp Ser Asp Gly Asp Gly Gly Ala Pro Asp Gln Tyr Trp Asn Ser225 230 235 240 Thr Gly Phe Leu Ala Trp Leu Tyr Asn Glu Ser Pro Val ArgGly Thr 245 250 255 Val Val Thr Asn Asp Arg Trp Gly Ala Gly Ser Ile CysLys His Gly 260 265 270 Gly Phe Tyr Thr Cys Ser Asp Arg Tyr Asn Pro GlyHis Leu Leu Pro 275 280 285 His Lys Trp Glu Asn Cys Met Thr Ile Asp LysLeu Ser Trp Gly Tyr 290 295 300 Arg Arg Glu Ala Gly Ile Ser Asp Tyr LeuThr Ile Glu Glu Leu Val 305 310 315 320 Lys Gln Leu Val Glu Thr Val SerCys Gly Gly Asn Leu Leu Met Asn 325 330 335 Ile Gly Pro Thr Leu Asp GlyThr Ile Ser Val Val Phe Glu Glu Arg 340 345 350 Leu Arg Gln Val Gly SerTrp Leu Lys Val Asn Gly Glu Ala Ile Tyr 355 360 365 Glu Thr Tyr Thr TrpArg Ser Gln Asn Asp Thr Val Thr Pro Asp Val 370 375 380 Trp Tyr Thr SerLys Pro Lys Glu Lys Leu Val Tyr Ala Ile Phe Leu 385 390 395 400 Lys TrpPro Thr Ser Gly Gln Leu Phe Leu Gly His Pro Lys Ala Ile 405 410 415 LeuGly Ala Thr Glu Val Lys Leu Leu Gly His Gly Gln Pro Leu Asn 420 425 430Trp Ile Ser Leu Glu Gln Asn Gly Ile Met Val Glu Leu Pro Gln Leu 435 440445 Thr Ile His Gln Met Pro Cys Lys Trp Gly Trp Ala Leu Ala Leu Thr 450455 460 Asn Val Ile 465 196 23 DNA Artificial Sequence Description ofArtificial Sequence Synthetic oligonucleotide probe 196 tggtttgaccaggccaagtt cgg 23 197 24 DNA Artificial Sequence Description ofArtificial Sequence Synthetic oligonucleotide probe 197 ggattcatcctcaaggaaga gcgg 24 198 24 DNA Artificial Sequence Description ofArtificial Sequence Synthetic oligonucleotide probe 198 aacttgcagcatcagccact ctgc 24 199 45 DNA Artificial Sequence Description ofArtificial Sequence Synthetic oligonucleotide probe 199 ttccgtgcccagcttcggta gcgagtggtt ctggtggtat tggca 45 200 2372 DNA Homo sapiens 200agcagggaaa tccggatgtc tcggttatga agtggagcag tgagtgtgag cctcaacata 60gttccagaac tctccatccg gactagttat tgagcatctg cctctcatat caccagtggc 120catctgaggt gtttccctgg ctctgaaggg gtaggcacga tggccaggtg cttcagcctg 180gtgttgcttc tcacttccat ctggaccacg aggctcctgg tccaaggctc tttgcgtgca 240gaagagcttt ccatccaggt gtcatgcaga attatgggga tcacccttgt gagcaaaaag 300gcgaaccagc agctgaattt cacagaagct aaggaggcct gtaggctgct gggactaagt 360ttggccggca aggaccaagt tgaaacagcc ttgaaagcta gctttgaaac ttgcagctat 420ggctgggttg gagatggatt cgtggtcatc tctaggatta gcccaaaccc caagtgtggg 480aaaaatgggg tgggtgtcct gatttggaag gttccagtga gccgacagtt tgcagcctat 540tgttacaact catctgatac ttggactaac tcgtgcattc cagaaattat caccaccaaa 600gatcccatat tcaacactca aactgcaaca caaacaacag aatttattgt cagtgacagt 660acctactcgg tggcatcccc ttactctaca atacctgccc ctactactac tcctcctgct 720ccagcttcca cttctattcc acggagaaaa aaattgattt gtgtcacaga agtttttatg 780gaaactagca ccatgtctac agaaactgaa ccatttgttg aaaataaagc agcattcaag 840aatgaagctg ctgggtttgg aggtgtcccc acggctctgc tagtgcttgc tctcctcttc 900tttggtgctg cagctggtct tggattttgc tatgtcaaaa ggtatgtgaa ggccttccct 960tttacaaaca agaatcagca gaaggaaatg atcgaaacca aagtagtaaa ggaggagaag 1020gccaatgata gcaaccctaa tgaggaatca aagaaaactg ataaaaaccc agaagagtcc 1080aagagtccaa gcaaaactac cgtgcgatgc ctggaagctg aagtttagat gagacagaaa 1140tgaggagaca cacctgaggc tggtttcttt catgctcctt accctgcccc agctggggaa 1200atcaaaaggg ccaaagaacc aaagaagaaa gtccaccctt ggttcctaac tggaatcagc 1260tcaggactgc cattggacta tggagtgcac caaagagaat gcccttctcc ttattgtaac 1320cctgtctgga tcctatcctc ctacctccaa agcttcccac ggcctttcta gcctggctat 1380gtcctaataa tatcccactg ggagaaagga gttttgcaaa gtgcaaggac ctaaaacatc 1440tcatcagtat ccagtggtaa aaaggcctcc tggctgtctg aggctaggtg ggttgaaagc 1500caaggagtca ctgagaccaa ggctttctct actgattccg cagctcagac cctttcttca 1560gctctgaaag agaaacacgt atcccacctg acatgtcctt ctgagcccgg taagagcaaa 1620agaatggcag aaaagtttag cccctgaaag ccatggagat tctcataact tgagacctaa 1680tctctgtaaa gctaaaataa agaaatagaa caaggctgag gatacgacag tacactgtca 1740gcagggactg taaacacaga cagggtcaaa gtgttttctc tgaacacatt gagttggaat 1800cactgtttag aacacacaca cttacttttt ctggtctcta ccactgctga tattttctct 1860aggaaatata cttttacaag taacaaaaat aaaaactctt ataaatttct atttttatct 1920gagttacaga aatgattact aaggaagatt actcagtaat ttgtttaaaa agtaataaaa 1980ttcaacaaac atttgctgaa tagctactat atgtcaagtg ctgtgcaagg tattacactc 2040tgtaattgaa tattattcct caaaaaattg cacatagtag aacgctatct gggaagctat 2100ttttttcagt tttgatattt ctagcttatc tacttccaaa ctaattttta tttttgctga 2160gactaatctt attcattttc tctaatatgg caaccattat aaccttaatt tattattaac 2220atacctaaga agtacattgt tacctctata taccaaagca cattttaaaa gtgccattaa 2280caaatgtatc actagccctc ctttttccaa caagaaggga ctgagagatg cagaaatatt 2340tgtgacaaaa aattaaagca tttagaaaac tt 2372 201 322 PRT Artificial sequenceSynthetic protein 201 Met Ala Arg Cys Phe Ser Leu Val Leu Leu Leu ThrSer Ile Trp Thr 1 5 10 15 Thr Arg Leu Leu Val Gln Gly Ser Leu Arg AlaGlu Glu Leu Ser Ile 20 25 30 Gln Val Ser Cys Arg Ile Met Gly Ile Thr LeuVal Ser Lys Lys Ala 35 40 45 Asn Gln Gln Leu Asn Phe Thr Glu Ala Lys GluAla Cys Arg Leu Leu 50 55 60 Gly Leu Ser Leu Ala Gly Lys Asp Gln Val GluThr Ala Leu Lys Ala 65 70 75 80 Ser Phe Glu Thr Cys Ser Tyr Gly Trp ValGly Asp Gly Phe Val Val 85 90 95 Ile Ser Arg Ile Ser Pro Asn Pro Lys CysGly Lys Asn Gly Val Gly 100 105 110 Val Leu Ile Trp Lys Val Pro Val SerArg Gln Phe Ala Ala Tyr Cys 115 120 125 Tyr Asn Ser Ser Asp Thr Trp ThrAsn Ser Cys Ile Pro Glu Ile Ile 130 135 140 Thr Thr Lys Asp Pro Ile PheAsn Thr Gln Thr Ala Thr Gln Thr Thr 145 150 155 160 Glu Phe Ile Val SerAsp Ser Thr Tyr Ser Val Ala Ser Pro Tyr Ser 165 170 175 Thr Ile Pro AlaPro Thr Thr Thr Pro Pro Ala Pro Ala Ser Thr Ser 180 185 190 Ile Pro ArgArg Lys Lys Leu Ile Cys Val Thr Glu Val Phe Met Glu 195 200 205 Thr SerThr Met Ser Thr Glu Thr Glu Pro Phe Val Glu Asn Lys Ala 210 215 220 AlaPhe Lys Asn Glu Ala Ala Gly Phe Gly Gly Val Pro Thr Ala Leu 225 230 235240 Leu Val Leu Ala Leu Leu Phe Phe Gly Ala Ala Ala Gly Leu Gly Phe 245250 255 Cys Tyr Val Lys Arg Tyr Val Lys Ala Phe Pro Phe Thr Asn Lys Asn260 265 270 Gln Gln Lys Glu Met Ile Glu Thr Lys Val Val Lys Glu Glu LysAla 275 280 285 Asn Asp Ser Asn Pro Asn Glu Glu Ser Lys Lys Thr Asp LysAsn Pro 290 295 300 Glu Glu Ser Lys Ser Pro Ser Lys Thr Thr Val Arg CysLeu Glu Ala 305 310 315 320 Glu Val 202 24 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe 202gagctttcca tccaggtgtc atgc 24 203 22 DNA Artificial Sequence Descriptionof Artificial Sequence Synthetic oligonucleotide probe 203 gtcagtgacagtacctactc gg 22 204 24 DNA Artificial Sequence Description ofArtificial Sequence Synthetic oligonucleotide probe 204 tggagcaggaggagtagtag tagg 24 205 50 DNA Artificial Sequence Description ofArtificial Sequence Synthetic oligonucleotide probe 205 aggaggcctgtaggctgctg ggactaagtt tggccggcaa ggaccaagtt 50 206 1620 DNA Homo sapiensmodified_base (973) a, t, c or g 206 agatggcggt cttggcacct ctaattgctctcgtgtattc ggtgccgcga ctttcacgat 60 ggctcgccca accttactac cttctgtcggccctgctctc tgctgccttc ctactcgtga 120 ggaaactgcc gccgctctgc cacggtctgcccacccaacg cgaagacggt aacccgtgtg 180 actttgactg gagagaagtg gagatcctgatgtttctcag tgccattgtg atgatgaaga 240 accgcagatc catcactgtg gagcaacatataggcaacat tttcatgttt agtaaagtgg 300 ccaacacaat tcttttcttc cgcttggatattcgcatggg cctactttac atcacactct 360 gcatagtgtt cctgatgacg tgcaaaccccccctatatat gggccctgag tatatcaagt 420 acttcaatga taaaaccatt gatgaggaactagaacggga caagagggtc acttggattg 480 tggagttctt tgccaattgg tctaatgactgccaatcatt tgcccctatc tatgctgacc 540 tctcccttaa atacaactgt acagggctaaattttgggaa ggtggatgtt ggacgctata 600 ctgatgttag tacgcggtac aaagtgagcacatcacccct caccaagcaa ctccctaccc 660 tgatcctgtt ccaaggtggc aaggaggcaatgcggcggcc acagattgac aagaaaggac 720 gggctgtctc atggaccttc tctgaggagaatgtgatccg agaatttaac ttaaatgagc 780 tataccagcg ggccaagaaa ctatcaaaggctggagacaa tatccctgag gagcagcctg 840 tggcttcaac ccccaccaca gtgtcagatggggaaaacaa gaaggataaa taagatcctc 900 actttggcag tgcttcctct cctgtcaattccaggctctt tccataacca caagcctgag 960 gctgcagcct ttnattnatg ttttccctttggctgngact ggntggggca gcatgcagct 1020 tctgatttta aagaggcatc tagggaattgtcaggcaccc tacaggaagg cctgccatgc 1080 tgtggccaac tgtttcactg gagcaagaaagagatctcat aggacggagg gggaaatggt 1140 ttccctccaa gcttgggtca gtgtgttaactgcttatcag ctattcagac atctccatgg 1200 tttctccatg aaactctgtg gtttcatcattccttcttag ttgacctgca cagcttggtt 1260 agacctagat ttaaccctaa ggtaagatgctggggtatag aacgctaaga attttccccc 1320 aaggactctt gcttccttaa gcccttctggcttcgtttat ggtcttcatt aaaagtataa 1380 gcctaacttt gtcgctagtc ctaaggagaaacctttaacc acaaagtttt tatcattgaa 1440 gacaatattg aacaaccccc tattttgtggggattgagaa ggggtgaata gaggcttgag 1500 actttccttt gtgtggtagg acttggaggagaaatcccct ggactttcac taaccctctg 1560 acatactccc cacacccagt tgatggctttccgtaataaa aagattggga tttccttttg 1620 207 296 PRT Homo sapiens 207 MetAla Val Leu Ala Pro Leu Ile Ala Leu Val Tyr Ser Val Pro Arg 1 5 10 15Leu Ser Arg Trp Leu Ala Gln Pro Tyr Tyr Leu Leu Ser Ala Leu Leu 20 25 30Ser Ala Ala Phe Leu Leu Val Arg Lys Leu Pro Pro Leu Cys His Gly 35 40 45Leu Pro Thr Gln Arg Glu Asp Gly Asn Pro Cys Asp Phe Asp Trp Arg 50 55 60Glu Val Glu Ile Leu Met Phe Leu Ser Ala Ile Val Met Met Lys Asn 65 70 7580 Arg Arg Ser Ile Thr Val Glu Gln His Ile Gly Asn Ile Phe Met Phe 85 9095 Ser Lys Val Ala Asn Thr Ile Leu Phe Phe Arg Leu Asp Ile Arg Met 100105 110 Gly Leu Leu Tyr Ile Thr Leu Cys Ile Val Phe Leu Met Thr Cys Lys115 120 125 Pro Pro Leu Tyr Met Gly Pro Glu Tyr Ile Lys Tyr Phe Asn AspLys 130 135 140 Thr Ile Asp Glu Glu Leu Glu Arg Asp Lys Arg Val Thr TrpIle Val 145 150 155 160 Glu Phe Phe Ala Asn Trp Ser Asn Asp Cys Gln SerPhe Ala Pro Ile 165 170 175 Tyr Ala Asp Leu Ser Leu Lys Tyr Asn Cys ThrGly Leu Asn Phe Gly 180 185 190 Lys Val Asp Val Gly Arg Tyr Thr Asp ValSer Thr Arg Tyr Lys Val 195 200 205 Ser Thr Ser Pro Leu Thr Lys Gln LeuPro Thr Leu Ile Leu Phe Gln 210 215 220 Gly Gly Lys Glu Ala Met Arg ArgPro Gln Ile Asp Lys Lys Gly Arg 225 230 235 240 Ala Val Ser Trp Thr PheSer Glu Glu Asn Val Ile Arg Glu Phe Asn 245 250 255 Leu Asn Glu Leu TyrGln Arg Ala Lys Lys Leu Ser Lys Ala Gly Asp 260 265 270 Asn Ile Pro GluGlu Gln Pro Val Ala Ser Thr Pro Thr Thr Val Ser 275 280 285 Asp Gly GluAsn Lys Lys Asp Lys 290 295 208 24 DNA Artificial Sequence Descriptionof Artificial Sequence Synthetic oligonucleotide probe 208 gcttggatattcgcatgggc ctac 24 209 20 DNA Artificial Sequence Description ofArtificial Sequence Synthetic oligonucleotide probe 209 tggagacaatatccctgagg 20 210 24 DNA Artificial Sequence Description of ArtificialSequence Synthetic oligonucleotide probe 210 aacagttggc cacagcatgg cagg24 211 50 DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 211 ccattgatga ggaactagaa cgggacaagagggtcacttg gattgtggag 50 212 1985 DNA Homo sapiens 212 ggacagctcgcggcccccga gagctctagc cgtcgaggag ctgcctgggg acgtttgccc 60 tggggccccagcctggcccg ggtcaccctg gcatgaggag atgggcctgt tgctcctggt 120 cccattgctcctgctgcccg gctcctacgg actgcccttc tacaacggct tctactactc 180 caacagcgccaacgaccaga acctaggcaa cggtcatggc aaagacctcc ttaatggagt 240 gaagctggtggtggagacac ccgaggagac cctgttcacc taccaagggg ccagtgtgat 300 cctgccctgccgctaccgct acgagccggc cctggtctcc ccgcggcgtg tgcgtgtcaa 360 atggtggaagctgtcggaga acggggcccc agagaaggac gtgctggtgg ccatcgggct 420 gaggcaccgctcctttgggg actaccaagg ccgcgtgcac ctgcggcagg acaaagagca 480 tgacgtctcgctggagatcc aggatctgcg gctggaggac tatgggcgtt accgctgtga 540 ggtcattgacgggctggagg atgaaagcgg tctggtggag ctggagctgc ggggtgtggt 600 ctttccttaccagtccccca acgggcgcta ccagttcaac ttccacgagg gccagcaggt 660 ctgtgcagagcaggctgcgg tggtggcctc ctttgagcag ctcttccggg cctgggagga 720 gggcctggactggtgcaacg cgggctggct gcaggatgct acggtgcagt accccatcat 780 gttgccccggcagccctgcg gtggcccagg cctggcacct ggcgtgcgaa gctacggccc 840 ccgccaccgccgcctgcacc gctatgatgt attctgcttc gctactgccc tcaaggggcg 900 ggtgtactacctggagcacc ctgagaagct gacgctgaca gaggcaaggg aggcctgcca 960 ggaagatgatgccacgatcg ccaaggtggg acagctcttt gccgcctgga agttccatgg 1020 cctggaccgctgcgacgctg gctggctggc agatggcagc gtccgctacc ctgtggttca 1080 cccgcatcctaactgtgggc ccccagagcc tggggtccga agctttggct tccccgaccc 1140 gcagagccgcttgtacggtg tttactgcta ccgccagcac taggacctgg ggccctcccc 1200 tgccgcattccctcactggc tgtgtattta ttgagtggtt cgttttccct tgtgggttgg 1260 agccattttaactgttttta tacttctcaa tttaaatttt ctttaaacat ttttttacta 1320 ttttttgtaaagcaaacaga acccaatgcc tccctttgct cctggatgcc ccactccagg 1380 aatcatgcttgctcccctgg gccatttgcg gttttgtggg cttctggagg gttccccgcc 1440 atccaggctggtctccctcc cttaaggagg ttggtgccca gagtgggcgg tggcctgtct 1500 agaatgccgccgggagtccg ggcatggtgg gcacagttct ccctgcccct cagcctgggg 1560 gaagaagagggcctcggggg cctccggagc tgggctttgg gcctctcctg cccacctcta 1620 cttctctgtgaagccgctga ccccagtctg cccactgagg ggctagggct ggaagccagt 1680 tctaggcttccaggcgaaat ctgagggaag gaagaaactc ccctccccgt tccccttccc 1740 ctctcggttccaaagaatct gttttgttgt catttgtttc tcctgtttcc ctgtgtgggg 1800 aggggccctcaggtgtgtgt actttggaca ataaatggtg ctatgactgc cttccgccaa 1860 aaaaaaaaaaaaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1920 aaaaaaaaaaaaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1980 aaaaa 1985213 360 PRT Homo sapiens 213 Met Gly Leu Leu Leu Leu Val Pro Leu Leu LeuLeu Pro Gly Ser Tyr 1 5 10 15 Gly Leu Pro Phe Tyr Asn Gly Phe Tyr TyrSer Asn Ser Ala Asn Asp 20 25 30 Gln Asn Leu Gly Asn Gly His Gly Lys AspLeu Leu Asn Gly Val Lys 35 40 45 Leu Val Val Glu Thr Pro Glu Glu Thr LeuPhe Thr Tyr Gln Gly Ala 50 55 60 Ser Val Ile Leu Pro Cys Arg Tyr Arg TyrGlu Pro Ala Leu Val Ser 65 70 75 80 Pro Arg Arg Val Arg Val Lys Trp TrpLys Leu Ser Glu Asn Gly Ala 85 90 95 Pro Glu Lys Asp Val Leu Val Ala IleGly Leu Arg His Arg Ser Phe 100 105 110 Gly Asp Tyr Gln Gly Arg Val HisLeu Arg Gln Asp Lys Glu His Asp 115 120 125 Val Ser Leu Glu Ile Gln AspLeu Arg Leu Glu Asp Tyr Gly Arg Tyr 130 135 140 Arg Cys Glu Val Ile AspGly Leu Glu Asp Glu Ser Gly Leu Val Glu 145 150 155 160 Leu Glu Leu ArgGly Val Val Phe Pro Tyr Gln Ser Pro Asn Gly Arg 165 170 175 Tyr Gln PheAsn Phe His Glu Gly Gln Gln Val Cys Ala Glu Gln Ala 180 185 190 Ala ValVal Ala Ser Phe Glu Gln Leu Phe Arg Ala Trp Glu Glu Gly 195 200 205 LeuAsp Trp Cys Asn Ala Gly Trp Leu Gln Asp Ala Thr Val Gln Tyr 210 215 220Pro Ile Met Leu Pro Arg Gln Pro Cys Gly Gly Pro Gly Leu Ala Pro 225 230235 240 Gly Val Arg Ser Tyr Gly Pro Arg His Arg Arg Leu His Arg Tyr Asp245 250 255 Val Phe Cys Phe Ala Thr Ala Leu Lys Gly Arg Val Tyr Tyr LeuGlu 260 265 270 His Pro Glu Lys Leu Thr Leu Thr Glu Ala Arg Glu Ala CysGln Glu 275 280 285 Asp Asp Ala Thr Ile Ala Lys Val Gly Gln Leu Phe AlaAla Trp Lys 290 295 300 Phe His Gly Leu Asp Arg Cys Asp Ala Gly Trp LeuAla Asp Gly Ser 305 310 315 320 Val Arg Tyr Pro Val Val His Pro His ProAsn Cys Gly Pro Pro Glu 325 330 335 Pro Gly Val Arg Ser Phe Gly Phe ProAsp Pro Gln Ser Arg Leu Tyr 340 345 350 Gly Val Tyr Cys Tyr Arg Gln His355 360 214 18 DNA Artificial Sequence Description of ArtificialSequence Synthetic oligonucleotide probe 214 tgcttcgcta ctgccctc 18 21518 DNA Artificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 215 ttcccttgtg ggttggag 18 216 18 DNA ArtificialSequence Description of Artificial Sequence Synthetic oligonucleotideprobe 216 agggctggaa gccagttc 18 217 18 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe 217agccagtgag gaaatgcg 18 218 24 DNA Artificial Sequence Description ofArtificial Sequence Synthetic oligonucleotide probe 218 tgtccaaagtacacacacct gagg 24 219 45 DNA Artificial Sequence Description ofArtificial Sequence Synthetic oligonucleotide probe 219 gatgccacgatcgccaaggt gggacagctc tttgccgcct ggaag 45 220 1503 DNA Homo sapiens 220ggagagcgga gcgaagctgg ataacagggg accgatgatg tggcgaccat cagttctgct 60gcttctgttg ctactgaggc acggggccca ggggaagcca tccccagacg caggccctca 120tggccagggg agggtgcacc aggcggcccc cctgagcgac gctccccatg atgacgccca 180cgggaacttc cagtacgacc atgaggcttt cctgggacgg gaagtggcca aggaattcga 240ccaactcacc ccagaggaaa gccaggcccg tctggggcgg atcgtggacc gcatggaccg 300cgcgggggac ggcgacggct gggtgtcgct ggccgagctt cgcgcgtgga tcgcgcacac 360gcagcagcgg cacatacggg actcggtgag cgcggcctgg gacacgtacg acacggaccg 420cgacgggcgt gtgggttggg aggagctgcg caacgccacc tatggccact acgcgcccgg 480tgaagaattt catgacgtgg aggatgcaga gacctacaaa aagatgctgg ctcgggacga 540gcggcgtttc cgggtggccg accaggatgg ggactcgatg gccactcgag aggagctgac 600agccttcctg caccccgagg agttccctca catgcgggac atcgtgattg ctgaaaccct 660ggaggacctg gacagaaaca aagatggcta tgtccaggtg gaggagtaca tcgcggatct 720gtactcagcc gagcctgggg aggaggagcc ggcgtgggtg cagacggaga ggcagcagtt 780ccgggacttc cgggatctga acaaggatgg gcacctggat gggagtgagg tgggccactg 840ggtgctgccc cctgcccagg accagcccct ggtggaagcc aaccacctgc tgcacgagag 900cgacacggac aaggatgggc ggctgagcaa agcggaaatc ctgggtaatt ggaacatgtt 960tgtgggcagt caggccacca actatggcga ggacctgacc cggcaccacg atgagctgtg 1020agcaccgcgc acctgccaca gcctcagagg cccgcacaat gaccggagga ggggccgctg 1080tggtctggcc ccctccctgt ccaggccccg caggaggcag atgcagtccc aggcatcctc 1140ctgcccctgg gctctcaggg accccctggg tcggcttctg tccctgtcac acccccaacc 1200ccagggaggg gctgtcatag tcccagagga taagcaatac ctatttctga ctgagtctcc 1260cagcccagac ccagggaccc ttggccccaa gctcagctct aagaaccgcc ccaacccctc 1320cagctccaaa tctgagcctc caccacatag actgaaactc ccctggcccc agccctctcc 1380tgcctggcct ggcctgggac acctcctctc tgccaggagg caataaaagc cagcgccggg 1440accttgaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1500aaa 1503 221 328 PRT Homo sapiens 221 Met Met Trp Arg Pro Ser Val LeuLeu Leu Leu Leu Leu Leu Arg His 1 5 10 15 Gly Ala Gln Gly Lys Pro SerPro Asp Ala Gly Pro His Gly Gln Gly 20 25 30 Arg Val His Gln Ala Ala ProLeu Ser Asp Ala Pro His Asp Asp Ala 35 40 45 His Gly Asn Phe Gln Tyr AspHis Glu Ala Phe Leu Gly Arg Glu Val 50 55 60 Ala Lys Glu Phe Asp Gln LeuThr Pro Glu Glu Ser Gln Ala Arg Leu 65 70 75 80 Gly Arg Ile Val Asp ArgMet Asp Arg Ala Gly Asp Gly Asp Gly Trp 85 90 95 Val Ser Leu Ala Glu LeuArg Ala Trp Ile Ala His Thr Gln Gln Arg 100 105 110 His Ile Arg Asp SerVal Ser Ala Ala Trp Asp Thr Tyr Asp Thr Asp 115 120 125 Arg Asp Gly ArgVal Gly Trp Glu Glu Leu Arg Asn Ala Thr Tyr Gly 130 135 140 His Tyr AlaPro Gly Glu Glu Phe His Asp Val Glu Asp Ala Glu Thr 145 150 155 160 TyrLys Lys Met Leu Ala Arg Asp Glu Arg Arg Phe Arg Val Ala Asp 165 170 175Gln Asp Gly Asp Ser Met Ala Thr Arg Glu Glu Leu Thr Ala Phe Leu 180 185190 His Pro Glu Glu Phe Pro His Met Arg Asp Ile Val Ile Ala Glu Thr 195200 205 Leu Glu Asp Leu Asp Arg Asn Lys Asp Gly Tyr Val Gln Val Glu Glu210 215 220 Tyr Ile Ala Asp Leu Tyr Ser Ala Glu Pro Gly Glu Glu Glu ProAla 225 230 235 240 Trp Val Gln Thr Glu Arg Gln Gln Phe Arg Asp Phe ArgAsp Leu Asn 245 250 255 Lys Asp Gly His Leu Asp Gly Ser Glu Val Gly HisTrp Val Leu Pro 260 265 270 Pro Ala Gln Asp Gln Pro Leu Val Glu Ala AsnHis Leu Leu His Glu 275 280 285 Ser Asp Thr Asp Lys Asp Gly Arg Leu SerLys Ala Glu Ile Leu Gly 290 295 300 Asn Trp Asn Met Phe Val Gly Ser GlnAla Thr Asn Tyr Gly Glu Asp 305 310 315 320 Leu Thr Arg His His Asp GluLeu 325 222 20 DNA Artificial Sequence Description of ArtificialSequence Synthetic oligonucleotide probe 222 cgcaggccct catggccagg 20223 18 DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 223 gaaatcctgg gtaattgg 18 224 23 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 224 gtgcgcggtg ctcacagctc atc 23 225 44 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 225 cccccctgag cgacgctccc ccatgatgac gcccacgggaactt 44 226 2403 DNA Homo sapiens 226 ggggccttgc cttccgcact cgggcgcagccgggtggatc tcgagcaggt gcggagcccc 60 gggcggcggg cgcgggtgcg agggatccctgacgcctctg tccctgtttc tttgtcgctc 120 ccagcctgtc tgtcgtcgtt ttggcgcccccgcctccccg cggtgcgggg ttgcacaccg 180 atcctgggct tcgctcgatt tgccgccgaggcgcctccca gacctagagg ggcgctggcc 240 tggagcagcg ggtcgtctgt gtcctctctcctctgcgccg cgcccgggga tccgaagggt 300 gcggggctct gaggaggtga cgcgcggggcctcccgcacc ctggccttgc ccgcattctc 360 cctctctccc aggtgtgagc agcctatcagtcaccatgtc cgcagcctgg atcccggctc 420 tcggcctcgg tgtgtgtctg ctgctgctgccggggcccgc gggcagcgag ggagccgctc 480 ccattgctat cacatgtttt accagaggcttggacatcag gaaagagaaa gcagatgtcc 540 tctgcccagg gggctgccct cttgaggaattctctgtgta tgggaacata gtatatgctt 600 ctgtatcgag catatgtggg gctgctgtccacaggggagt aatcagcaac tcagggggac 660 ctgtacgagt ctatagccta cctggtcgagaaaactattc ctcagtagat gccaatggca 720 tccagtctca aatgctttct agatggtctgcttctttcac agtaactaaa ggcaaaagta 780 gtacacagga ggccacagga caagcagtgtccacagcaca tccaccaaca ggtaaacgac 840 taaagaaaac acccgagaag aaaactggcaataaagattg taaagcagac attgcatttc 900 tgattgatgg aagctttaat attgggcagcgccgatttaa tttacagaag aattttgttg 960 gaaaagtggc tctaatgttg ggaattggaacagaaggacc acatgtgggc cttgttcaag 1020 ccagtgaaca tcccaaaata gaattttacttgaaaaactt tacatcagcc aaagatgttt 1080 tgtttgccat aaaggaagta ggtttcagagggggtaattc caatacagga aaagccttga 1140 agcatactgc tcagaaattc ttcacggtagatgctggagt aagaaaaggg atccccaaag 1200 tggtggtggt atttattgat ggttggccttctgatgacat cgaggaagca ggcattgtgg 1260 ccagagagtt tggtgtcaat gtatttatagtttctgtggc caagcctatc cctgaagaac 1320 tggggatggt tcaggatgtc acatttgttgacaaggctgt ctgtcggaat aatggcttct 1380 tctcttacca catgcccaac tggtttggcaccacaaaata cgtaaagcct ctggtacaga 1440 agctgtgcac tcatgaacaa atgatgtgcagcaagacctg ttataactca gtgaacattg 1500 cctttctaat tgatggctcc agcagtgttggagatagcaa tttccgcctc atgcttgaat 1560 ttgtttccaa catagccaag acttttgaaatctcggacat tggtgccaag atagctgctg 1620 tacagtttac ttatgatcag cgcacggagttcagtttcac tgactatagc accaaagaga 1680 atgtcctagc tgtcatcaga aacatccgctatatgagtgg tggaacagct actggtgatg 1740 ccatttcctt cactgttaga aatgtgtttggccctataag ggagagcccc aacaagaact 1800 tcctagtaat tgtcacagat gggcagtcctatgatgatgt ccaaggccct gcagctgctg 1860 cacatgatgc aggaatcact atcttctctgttggtgtggc ttgggcacct ctggatgacc 1920 tgaaagatat ggcttctaaa ccgaaggagtctcacgcttt cttcacaaga gagttcacag 1980 gattagaacc aattgtttct gatgtcatcagaggcatttg tagagatttc ttagaatccc 2040 agcaataatg gtaacatttt gacaactgaaagaaaaagta caaggggatc cagtgtgtaa 2100 attgtattct cataatactg aaatgctttagcatactaga atcagataca aaactattaa 2160 gtatgtcaac agccatttag gcaaataagcactcctttaa agccgctgcc ttctggttac 2220 aatttacagt gtactttgtt aaaaacactgctgaggcttc ataatcatgg ctcttagaaa 2280 ctcaggaaag aggagataat gtggattaaaaccttaagag ttctaaccat gcctactaaa 2340 tgtacagata tgcaaattcc atagctcaataaaagaatct gatacttaga ccaaaaaaaa 2400 aaa 2403 227 550 PRT Homo sapiens227 Met Ser Ala Ala Trp Ile Pro Ala Leu Gly Leu Gly Val Cys Leu Leu 1 510 15 Leu Leu Pro Gly Pro Ala Gly Ser Glu Gly Ala Ala Pro Ile Ala Ile 2025 30 Thr Cys Phe Thr Arg Gly Leu Asp Ile Arg Lys Glu Lys Ala Asp Val 3540 45 Leu Cys Pro Gly Gly Cys Pro Leu Glu Glu Phe Ser Val Tyr Gly Asn 5055 60 Ile Val Tyr Ala Ser Val Ser Ser Ile Cys Gly Ala Ala Val His Arg 6570 75 80 Gly Val Ile Ser Asn Ser Gly Gly Pro Val Arg Val Tyr Ser Leu Pro85 90 95 Gly Arg Glu Asn Tyr Ser Ser Val Asp Ala Asn Gly Ile Gln Ser Gln100 105 110 Met Leu Ser Arg Trp Ser Ala Ser Phe Thr Val Thr Lys Gly LysSer 115 120 125 Ser Thr Gln Glu Ala Thr Gly Gln Ala Val Ser Thr Ala HisPro Pro 130 135 140 Thr Gly Lys Arg Leu Lys Lys Thr Pro Glu Lys Lys ThrGly Asn Lys 145 150 155 160 Asp Cys Lys Ala Asp Ile Ala Phe Leu Ile AspGly Ser Phe Asn Ile 165 170 175 Gly Gln Arg Arg Phe Asn Leu Gln Lys AsnPhe Val Gly Lys Val Ala 180 185 190 Leu Met Leu Gly Ile Gly Thr Glu GlyPro His Val Gly Leu Val Gln 195 200 205 Ala Ser Glu His Pro Lys Ile GluPhe Tyr Leu Lys Asn Phe Thr Ser 210 215 220 Ala Lys Asp Val Leu Phe AlaIle Lys Glu Val Gly Phe Arg Gly Gly 225 230 235 240 Asn Ser Asn Thr GlyLys Ala Leu Lys His Thr Ala Gln Lys Phe Phe 245 250 255 Thr Val Asp AlaGly Val Arg Lys Gly Ile Pro Lys Val Val Val Val 260 265 270 Phe Ile AspGly Trp Pro Ser Asp Asp Ile Glu Glu Ala Gly Ile Val 275 280 285 Ala ArgGlu Phe Gly Val Asn Val Phe Ile Val Ser Val Ala Lys Pro 290 295 300 IlePro Glu Glu Leu Gly Met Val Gln Asp Val Thr Phe Val Asp Lys 305 310 315320 Ala Val Cys Arg Asn Asn Gly Phe Phe Ser Tyr His Met Pro Asn Trp 325330 335 Phe Gly Thr Thr Lys Tyr Val Lys Pro Leu Val Gln Lys Leu Cys Thr340 345 350 His Glu Gln Met Met Cys Ser Lys Thr Cys Tyr Asn Ser Val AsnIle 355 360 365 Ala Phe Leu Ile Asp Gly Ser Ser Ser Val Gly Asp Ser AsnPhe Arg 370 375 380 Leu Met Leu Glu Phe Val Ser Asn Ile Ala Lys Thr PheGlu Ile Ser 385 390 395 400 Asp Ile Gly Ala Lys Ile Ala Ala Val Gln PheThr Tyr Asp Gln Arg 405 410 415 Thr Glu Phe Ser Phe Thr Asp Tyr Ser ThrLys Glu Asn Val Leu Ala 420 425 430 Val Ile Arg Asn Ile Arg Tyr Met SerGly Gly Thr Ala Thr Gly Asp 435 440 445 Ala Ile Ser Phe Thr Val Arg AsnVal Phe Gly Pro Ile Arg Glu Ser 450 455 460 Pro Asn Lys Asn Phe Leu ValIle Val Thr Asp Gly Gln Ser Tyr Asp 465 470 475 480 Asp Val Gln Gly ProAla Ala Ala Ala His Asp Ala Gly Ile Thr Ile 485 490 495 Phe Ser Val GlyVal Ala Trp Ala Pro Leu Asp Asp Leu Lys Asp Met 500 505 510 Ala Ser LysPro Lys Glu Ser His Ala Phe Phe Thr Arg Glu Phe Thr 515 520 525 Gly LeuGlu Pro Ile Val Ser Asp Val Ile Arg Gly Ile Cys Arg Asp 530 535 540 PheLeu Glu Ser Gln Gln 545 550 228 18 DNA Artificial Sequence Descriptionof Artificial Sequence Synthetic oligonucleotide probe 228 tggtctcgcacaccgatc 18 229 18 DNA Artificial Sequence Description of ArtificialSequence Synthetic oligonucleotide probe 229 ctgctgtcca caggggag 18 23018 DNA Artificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 230 ccttgaagca tactgctc 18 231 18 DNA ArtificialSequence Description of Artificial Sequence Synthetic oligonucleotideprobe 231 gagatagcaa tttccgcc 18 232 18 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe 232ttcctcaaga gggcagcc 18 233 24 DNA Artificial Sequence Description ofArtificial Sequence Synthetic oligonucleotide probe 233 cttggcaccaatgtccgaga tttc 24 234 45 DNA Artificial Sequence Description ofArtificial Sequence Synthetic oligonucleotide probe 234 gctctgaggaaggtgacgcg cggggcctcc gaacccttgg ccttg 45 235 2586 DNA Homo sapiens 235cgccgcgctc ccgcacccgc ggcccgccca ccgcgccgct cccgcatctg cacccgcagc 60ccggcggcct cccggcggga gcgagcagat ccagtccggc ccgcagcgca actcggtcca 120gtcggggcgg cggctgcggg cgcagagcgg agatgcagcg gcttggggcc accctgctgt 180gcctgctgct ggcggcggcg gtccccacgg cccccgcgcc cgctccgacg gcgacctcgg 240ctccagtcaa gcccggcccg gctctcagct acccgcagga ggaggccacc ctcaatgaga 300tgttccgcga ggttgaggaa ctgatggagg acacgcagca caaattgcgc agcgcggtgg 360aagagatgga ggcagaagaa gctgctgcta aagcatcatc agaagtgaac ctggcaaact 420tacctcccag ctatcacaat gagaccaaca cagacacgaa ggttggaaat aataccatcc 480atgtgcaccg agaaattcac aagataacca acaaccagac tggacaaatg gtcttttcag 540agacagttat cacatctgtg ggagacgaag aaggcagaag gagccacgag tgcatcatcg 600acgaggactg tgggcccagc atgtactgcc agtttgccag cttccagtac acctgccagc 660catgccgggg ccagaggatg ctctgcaccc gggacagtga gtgctgtgga gaccagctgt 720gtgtctgggg tcactgcacc aaaatggcca ccaggggcag caatgggacc atctgtgaca 780accagaggga ctgccagccg gggctgtgct gtgccttcca gagaggcctg ctgttccctg 840tgtgcacacc cctgcccgtg gagggcgagc tttgccatga ccccgccagc cggcttctgg 900acctcatcac ctgggagcta gagcctgatg gagccttgga ccgatgccct tgtgccagtg 960gcctcctctg ccagccccac agccacagcc tggtgtatgt gtgcaagccg accttcgtgg 1020ggagccgtga ccaagatggg gagatcctgc tgcccagaga ggtccccgat gagtatgaag 1080ttggcagctt catggaggag gtgcgccagg agctggagga cctggagagg agcctgactg 1140aagagatggc gctgggggag cctgcggctg ccgccgctgc actgctggga ggggaagaga 1200tttagatctg gaccaggctg tgggtagatg tgcaatagaa atagctaatt tatttcccca 1260ggtgtgtgct ttaggcgtgg gctgaccagg cttcttccta catcttcttc ccagtaagtt 1320tcccctctgg cttgacagca tgaggtgttg tgcatttgtt cagctccccc aggctgttct 1380ccaggcttca cagtctggtg cttgggagag tcaggcaggg ttaaactgca ggagcagttt 1440gccacccctg tccagattat tggctgcttt gcctctacca gttggcagac agccgtttgt 1500tctacatggc tttgataatt gtttgagggg aggagatgga aacaatgtgg agtctccctc 1560tgattggttt tggggaaatg tggagaagag tgccctgctt tgcaaacatc aacctggcaa 1620aaatgcaaca aatgaatttt ccacgcagtt ctttccatgg gcataggtaa gctgtgcctt 1680cagctgttgc agatgaaatg ttctgttcac cctgcattac atgtgtttat tcatccagca 1740gtgttgctca gctcctacct ctgtgccagg gcagcatttt catatccaag atcaattccc 1800tctctcagca cagcctgggg agggggtcat tgttctcctc gtccatcagg gatctcagag 1860gctcagagac tgcaagctgc ttgcccaagt cacacagcta gtgaagacca gagcagtttc 1920atctggttgt gactctaagc tcagtgctct ctccactacc ccacaccagc cttggtgcca 1980ccaaaagtgc tccccaaaag gaaggagaat gggatttttc ttgaggcatg cacatctgga 2040attaaggtca aactaattct cacatccctc taaaagtaaa ctactgttag gaacagcagt 2100gttctcacag tgtggggcag ccgtccttct aatgaagaca atgatattga cactgtccct 2160ctttggcagt tgcattagta actttgaaag gtatatgact gagcgtagca tacaggttaa 2220cctgcagaaa cagtacttag gtaattgtag ggcgaggatt ataaatgaaa tttgcaaaat 2280cacttagcag caactgaaga caattatcaa ccacgtggag aaaatcaaac cgagcagggc 2340tgtgtgaaac atggttgtaa tatgcgactg cgaacactga actctacgcc actccacaaa 2400tgatgttttc aggtgtcatg gactgttgcc accatgtatt catccagagt tcttaaagtt 2460taaagttgca catgattgta taagcatgct ttctttgagt tttaaattat gtataaacat 2520aagttgcatt tagaaatcaa gcataaatca cttcaactgc aaaaaaaaaa aaaaaaaaaa 2580aaaaaa 2586 236 350 PRT Homo sapiens 236 Met Gln Arg Leu Gly Ala Thr LeuLeu Cys Leu Leu Leu Ala Ala Ala 1 5 10 15 Val Pro Thr Ala Pro Ala ProAla Pro Thr Ala Thr Ser Ala Pro Val 20 25 30 Lys Pro Gly Pro Ala Leu SerTyr Pro Gln Glu Glu Ala Thr Leu Asn 35 40 45 Glu Met Phe Arg Glu Val GluGlu Leu Met Glu Asp Thr Gln His Lys 50 55 60 Leu Arg Ser Ala Val Glu GluMet Glu Ala Glu Glu Ala Ala Ala Lys 65 70 75 80 Ala Ser Ser Glu Val AsnLeu Ala Asn Leu Pro Pro Ser Tyr His Asn 85 90 95 Glu Thr Asn Thr Asp ThrLys Val Gly Asn Asn Thr Ile His Val His 100 105 110 Arg Glu Ile His LysIle Thr Asn Asn Gln Thr Gly Gln Met Val Phe 115 120 125 Ser Glu Thr ValIle Thr Ser Val Gly Asp Glu Glu Gly Arg Arg Ser 130 135 140 His Glu CysIle Ile Asp Glu Asp Cys Gly Pro Ser Met Tyr Cys Gln 145 150 155 160 PheAla Ser Phe Gln Tyr Thr Cys Gln Pro Cys Arg Gly Gln Arg Met 165 170 175Leu Cys Thr Arg Asp Ser Glu Cys Cys Gly Asp Gln Leu Cys Val Trp 180 185190 Gly His Cys Thr Lys Met Ala Thr Arg Gly Ser Asn Gly Thr Ile Cys 195200 205 Asp Asn Gln Arg Asp Cys Gln Pro Gly Leu Cys Cys Ala Phe Gln Arg210 215 220 Gly Leu Leu Phe Pro Val Cys Thr Pro Leu Pro Val Glu Gly GluLeu 225 230 235 240 Cys His Asp Pro Ala Ser Arg Leu Leu Asp Leu Ile ThrTrp Glu Leu 245 250 255 Glu Pro Asp Gly Ala Leu Asp Arg Cys Pro Cys AlaSer Gly Leu Leu 260 265 270 Cys Gln Pro His Ser His Ser Leu Val Tyr ValCys Lys Pro Thr Phe 275 280 285 Val Gly Ser Arg Asp Gln Asp Gly Glu IleLeu Leu Pro Arg Glu Val 290 295 300 Pro Asp Glu Tyr Glu Val Gly Ser PheMet Glu Glu Val Arg Gln Glu 305 310 315 320 Leu Glu Asp Leu Glu Arg SerLeu Thr Glu Glu Met Ala Leu Gly Glu 325 330 335 Pro Ala Ala Ala Ala AlaAla Leu Leu Gly Gly Glu Glu Ile 340 345 350 237 17 DNA ArtificialSequence Synthetic oligonucleotide probe 237 ggagctgcac cccttgc 17 23849 DNA Artificial Sequence Synthetic Oligonucleotide Probe 238ggaggactgt gccaccatga gagactcttc aaacccaagg caaaattgg 49 239 24 DNAArtificial Sequence Synthetic Oligonucleotide Probe 239 gcagagcggagatgcagcgg cttg 24 240 18 DNA Artificial Sequence SyntheticOligonucleotide Probe 240 ttggcagctt catggagg 18 241 18 DNA ArtificialSequence Synthetic Oligonucleotide Probe 241 cctgggcaaa aatgcaac 18 24224 DNA Artificial Sequence Synthetic Oligonucleotide Probe 242ctccagctcc tggcgcacct cctc 24 243 45 DNA Artificial Sequence SyntheticOligonucleotide Probe 243 ggctctcagc taccgcgcag gagcgaggcc accctcaatgagatg 45 244 3679 DNA Homo Sapien 244 aaggaggctg ggaggaaaga ggtaagaaaggttagagaac ctacctcaca 50 tctctctggg ctcagaagga ctctgaagat aacaataatttcagcccatc 100 cactctcctt ccctcccaaa cacacatgtg catgtacaca cacacataca150 cacacataca ccttcctctc cttcactgaa gactcacagt cactcactct 200gtgagcaggt catagaaaag gacactaaag ccttaaggac aggcctggcc 250 attacctctgcagctccttt ggcttgttga gtcaaaaaac atgggagggg 300 ccaggcacgg tgactcacacctgtaatccc agcattttgg gagaccgagg 350 tgagcagatc acttgaggtc aggagttcgagaccagcctg gccaacatgg 400 agaaaccccc atctctacta aaaatacaaa aattagccaggagtggtggc 450 aggtgcctgt aatcccagct actcaggtgg ctgagccagg agaatcgctt500 gaatccagga ggcggaggat gcagtcagct gagtgcaccg ctgcactcca 550gcctgggtga cagaatgaga ctctgtctca aacaaacaaa cacgggagga 600 ggggtagatactgcttctct gcaacctcct taactctgca tcctcttctt 650 ccagggctgc ccctgatggggcctggcaat gactgagcag gcccagcccc 700 agaggacaag gaagagaagg catattgaggagggcaagaa gtgacgcccg 750 gtgtagaatg actgccctgg gagggtggtt ccttgggccctggcagggtt 800 gctgaccctt accctgcaaa acacaaagag caggactcca gactctcctt850 gtgaatggtc ccctgccctg cagctccacc atgaggcttc tcgtggcccc 900actcttgcta gcttgggtgg ctggtgccac tgccactgtg cccgtggtac 950 cctggcatgttccctgcccc cctcagtgtg cctgccagat ccggccctgg 1000 tatacgcccc gctcgtcctaccgcgaggct accactgtgg actgcaatga 1050 cctattcctg acggcagtcc ccccggcactccccgcaggc acacagaccc 1100 tgctcctgca gagcaacagc attgtccgtg tggaccagagtgagctgggc 1150 tacctggcca atctcacaga gctggacctg tcccagaaca gcttttcgga1200 tgcccgagac tgtgatttcc atgccctgcc ccagctgctg agcctgcacc 1250tagaggagaa ccagctgacc cggctggagg accacagctt tgcagggctg 1300 gccagcctacaggaactcta tctcaaccac aaccagctct accgcatcgc 1350 ccccagggcc ttttctggcctcagcaactt gctgcggctg cacctcaact 1400 ccaacctcct gagggccatt gacagccgctggtttgaaat gctgcccaac 1450 ttggagatac tcatgattgg cggcaacaag gtagatgccatcctggacat 1500 gaacttccgg cccctggcca acctgcgtag cctggtgcta gcaggcatga1550 acctgcggga gatctccgac tatgccctgg aggggctgca aagcctggag 1600agcctctcct tctatgacaa ccagctggcc cgggtgccca ggcgggcact 1650 ggaacaggtgcccgggctca agttcctaga cctcaacaag aacccgctcc 1700 agcgggtagg gccgggggactttgccaaca tgctgcacct taaggagctg 1750 ggactgaaca acatggagga gctggtctccatcgacaagt ttgccctggt 1800 gaacctcccc gagctgacca agctggacat caccaataacccacggctgt 1850 ccttcatcca cccccgcgcc ttccaccacc tgccccagat ggagaccctc1900 atgctcaaca acaacgctct cagtgccttg caccagcaga cggtggagtc 1950cctgcccaac ctgcaggagg taggtctcca cggcaacccc atccgctgtg 2000 actgtgtcatccgctgggcc aatgccacgg gcacccgtgt ccgcttcatc 2050 gagccgcaat ccaccctgtgtgcggagcct ccggacctcc agcgcctccc 2100 ggtccgtgag gtgcccttcc gggagatgacggaccactgt ttgcccctca 2150 tctccccacg aagcttcccc ccaagcctcc aggtagccagtggagagagc 2200 atggtgctgc attgccgggc actggccgaa cccgaacccg agatctactg2250 ggtcactcca gctgggcttc gactgacacc tgcccatgca ggcaggaggt 2300accgggtgta ccccgagggg accctggagc tgcggagggt gacagcagaa 2350 gaggcagggctatacacctg tgtggcccag aacctggtgg gggctgacac 2400 taagacggtt agtgtggttgtgggccgtgc tctcctccag ccaggcaggg 2450 acgaaggaca ggggctggag ctccgggtgcaggagaccca cccctatcac 2500 atcctgctat cttgggtcac cccacccaac acagtgtccaccaacctcac 2550 ctggtccagt gcctcctccc tccggggcca gggggccaca gctctggccc2600 gcctgcctcg gggaacccac agctacaaca ttacccgcct ccttcaggcc 2650acggagtact gggcctgcct gcaagtggcc tttgctgatg cccacaccca 2700 gttggcttgtgtatgggcca ggaccaaaga ggccacttct tgccacagag 2750 ccttagggga tcgtcctgggctcattgcca tcctggctct cgctgtcctt 2800 ctcctggcag ctgggctagc ggcccaccttggcacaggcc aacccaggaa 2850 gggtgtgggt gggaggcggc ctctccctcc agcctgggctttctggggct 2900 ggagtgcccc ttctgtccgg gttgtgtctg ctcccctcgt cctgccctgg2950 aatccaggga ggaagctgcc cagatcctca gaaggggaga cactgttgcc 3000accattgtct caaaattctt gaagctcagc ctgttctcag cagtagagaa 3050 atcactaggactacttttta ccaaaagaga agcagtctgg gccagatgcc 3100 ctgccaggaa agggacatggacccacgtgc ttgaggcctg gcagctgggc 3150 caagacagat ggggctttgt ggccctgggggtgcttctgc agccttgaaa 3200 aagttgccct tacctcctag ggtcacctct gctgccattctgaggaacat 3250 ctccaaggaa caggagggac tttggctaga gcctcctgcc tccccatctt3300 ctctctgccc agaggctcct gggcctggct tggctgtccc ctacctgtgt 3350ccccgggctg caccccttcc tcttctcttt ctctgtacag tctcagttgc 3400 ttgctcttgtgcctcctggg caagggctga aggaggccac tccatctcac 3450 ctcggggggc tgccctcaatgtgggagtga ccccagccag atctgaagga 3500 catttgggag agggatgccc aggaacgcctcatctcagca gcctgggctc 3550 ggcattccga agctgacttt ctataggcaa ttttgtacctttgtggagaa 3600 atgtgtcacc tcccccaacc cgattcactc ttttctcctg ttttgtaaaa3650 aataaaaata aataataaca ataaaaaaa 3679 245 713 PRT Homo Sapien 245Met Arg Leu Leu Val Ala Pro Leu Leu Leu Ala Trp Val Ala Gly 1 5 10 15Ala Thr Ala Thr Val Pro Val Val Pro Trp His Val Pro Cys Pro 20 25 30 ProGln Cys Ala Cys Gln Ile Arg Pro Trp Tyr Thr Pro Arg Ser 35 40 45 Ser TyrArg Glu Ala Thr Thr Val Asp Cys Asn Asp Leu Phe Leu 50 55 60 Thr Ala ValPro Pro Ala Leu Pro Ala Gly Thr Gln Thr Leu Leu 65 70 75 Leu Gln Ser AsnSer Ile Val Arg Val Asp Gln Ser Glu Leu Gly 80 85 90 Tyr Leu Ala Asn LeuThr Glu Leu Asp Leu Ser Gln Asn Ser Phe 95 100 105 Ser Asp Ala Arg AspCys Asp Phe His Ala Leu Pro Gln Leu Leu 110 115 120 Ser Leu His Leu GluGlu Asn Gln Leu Thr Arg Leu Glu Asp His 125 130 135 Ser Phe Ala Gly LeuAla Ser Leu Gln Glu Leu Tyr Leu Asn His 140 145 150 Asn Gln Leu Tyr ArgIle Ala Pro Arg Ala Phe Ser Gly Leu Ser 155 160 165 Asn Leu Leu Arg LeuHis Leu Asn Ser Asn Leu Leu Arg Ala Ile 170 175 180 Asp Ser Arg Trp PheGlu Met Leu Pro Asn Leu Glu Ile Leu Met 185 190 195 Ile Gly Gly Asn LysVal Asp Ala Ile Leu Asp Met Asn Phe Arg 200 205 210 Pro Leu Ala Asn LeuArg Ser Leu Val Leu Ala Gly Met Asn Leu 215 220 225 Arg Glu Ile Ser AspTyr Ala Leu Glu Gly Leu Gln Ser Leu Glu 230 235 240 Ser Leu Ser Phe TyrAsp Asn Gln Leu Ala Arg Val Pro Arg Arg 245 250 255 Ala Leu Glu Gln ValPro Gly Leu Lys Phe Leu Asp Leu Asn Lys 260 265 270 Asn Pro Leu Gln ArgVal Gly Pro Gly Asp Phe Ala Asn Met Leu 275 280 285 His Leu Lys Glu LeuGly Leu Asn Asn Met Glu Glu Leu Val Ser 290 295 300 Ile Asp Lys Phe AlaLeu Val Asn Leu Pro Glu Leu Thr Lys Leu 305 310 315 Asp Ile Thr Asn AsnPro Arg Leu Ser Phe Ile His Pro Arg Ala 320 325 330 Phe His His Leu ProGln Met Glu Thr Leu Met Leu Asn Asn Asn 335 340 345 Ala Leu Ser Ala LeuHis Gln Gln Thr Val Glu Ser Leu Pro Asn 350 355 360 Leu Gln Glu Val GlyLeu His Gly Asn Pro Ile Arg Cys Asp Cys 365 370 375 Val Ile Arg Trp AlaAsn Ala Thr Gly Thr Arg Val Arg Phe Ile 380 385 390 Glu Pro Gln Ser ThrLeu Cys Ala Glu Pro Pro Asp Leu Gln Arg 395 400 405 Leu Pro Val Arg GluVal Pro Phe Arg Glu Met Thr Asp His Cys 410 415 420 Leu Pro Leu Ile SerPro Arg Ser Phe Pro Pro Ser Leu Gln Val 425 430 435 Ala Ser Gly Glu SerMet Val Leu His Cys Arg Ala Leu Ala Glu 440 445 450 Pro Glu Pro Glu IleTyr Trp Val Thr Pro Ala Gly Leu Arg Leu 455 460 465 Thr Pro Ala His AlaGly Arg Arg Tyr Arg Val Tyr Pro Glu Gly 470 475 480 Thr Leu Glu Leu ArgArg Val Thr Ala Glu Glu Ala Gly Leu Tyr 485 490 495 Thr Cys Val Ala GlnAsn Leu Val Gly Ala Asp Thr Lys Thr Val 500 505 510 Ser Val Val Val GlyArg Ala Leu Leu Gln Pro Gly Arg Asp Glu 515 520 525 Gly Gln Gly Leu GluLeu Arg Val Gln Glu Thr His Pro Tyr His 530 535 540 Ile Leu Leu Ser TrpVal Thr Pro Pro Asn Thr Val Ser Thr Asn 545 550 555 Leu Thr Trp Ser SerAla Ser Ser Leu Arg Gly Gln Gly Ala Thr 560 565 570 Ala Leu Ala Arg LeuPro Arg Gly Thr His Ser Tyr Asn Ile Thr 575 580 585 Arg Leu Leu Gln AlaThr Glu Tyr Trp Ala Cys Leu Gln Val Ala 590 595 600 Phe Ala Asp Ala HisThr Gln Leu Ala Cys Val Trp Ala Arg Thr 605 610 615 Lys Glu Ala Thr SerCys His Arg Ala Leu Gly Asp Arg Pro Gly 620 625 630 Leu Ile Ala Ile LeuAla Leu Ala Val Leu Leu Leu Ala Ala Gly 635 640 645 Leu Ala Ala His LeuGly Thr Gly Gln Pro Arg Lys Gly Val Gly 650 655 660 Gly Arg Arg Pro LeuPro Pro Ala Trp Ala Phe Trp Gly Trp Ser 665 670 675 Ala Pro Ser Val ArgVal Val Ser Ala Pro Leu Val Leu Pro Trp 680 685 690 Asn Pro Gly Arg LysLeu Pro Arg Ser Ser Glu Gly Glu Thr Leu 695 700 705 Leu Pro Pro Leu SerGln Asn Ser 710 246 22 DNA Artificial Sequence Synthetic OligonucleotideProbe 246 aacaaggtaa gatgccatcc tg 22 247 24 DNA Artificial SequenceSynthetic Oligonucleotide Probe 247 aaacttgtcg atggagacca gctc 24 248 45DNA Artificial Sequence Synthetic Oligonucleotide Probe 248 aggggctgcaaagcctggag agcctctcct tctatgacaa ccagc 45 249 3401 DNA Homo Sapien 249gcaagccaag gcgctgtttg agaaggtgaa gaagttccgg acccatgtgg 50 aggagggggacattgtgtac cgcctctaca tgcggcagac catcatcaag 100 gtgatcaagt tcatcctcatcatctgctac accgtctact acgtgcacaa 150 catcaagttc gacgtggact gcaccgtggacattgagagc ctgacgggct 200 accgcaccta ccgctgtgcc caccccctgg ccacactcttcaagatcctg 250 gcgtccttct acatcagcct agtcatcttc tacggcctca tctgcatgta300 cacactgtgg tggatgctac ggcgctccct caagaagtac tcgtttgagt 350cgatccgtga ggagagcagc tacagcgaca tccccgacgt caagaacgac 400 ttcgccttcatgctgcacct cattgaccaa tacgacccgc tctactccaa 450 gcgcttcgcc gtcttcctgtcggaggtgag tgagaacaag ctgcggcagc 500 tgaacctcaa caacgagtgg acgctggacaagctccggca gcggctcacc 550 aagaacgcgc aggacaagct ggagctgcac ctgttcatgctcagtggcat 600 ccctgacact gtgtttgacc tggtggagct ggaggtcctc aagctggagc650 tgatccccga cgtgaccatc ccgcccagca ttgcccagct cacgggcctc 700aaggagctgt ggctctacca cacagcggcc aagattgaag cgcctgcgct 750 ggccttcctgcgcgagaacc tgcgggcgct gcacatcaag ttcaccgaca 800 tcaaggagat cccgctgtggatctatagcc tgaagacact ggaggagctg 850 cacctgacgg gcaacctgag cgcggagaacaaccgctaca tcgtcatcga 900 cgggctgcgg gagctcaaac gcctcaaggt gctgcggctcaagagcaacc 950 taagcaagct gccacaggtg gtcacagatg tgggcgtgca cctgcagaag1000 ctgtccatca acaatgaggg caccaagctc atcgtcctca acagcctcaa 1050gaagatggcg aacctgactg agctggagct gatccgctgc gacctggagc 1100 gcatcccccactccatcttc agcctccaca acctgcagga gattgacctc 1150 aaggacaaca acctcaagaccatcgaggag atcatcagct tccagcacct 1200 gcaccgcctc acctgcctta agctgtggtacaaccacatc gcctacatcc 1250 ccatccagat cggcaacctc accaacctgg agcgcctctacctgaaccgc 1300 aacaagatcg agaagatccc cacccagctc ttctactgcc gcaagctgcg1350 ctacctggac ctcagccaca acaacctgac cttcctccct gccgacatcg 1400gcctcctgca gaacctccag aacctagcca tcacggccaa ccggatcgag 1450 acgctccctccggagctctt ccagtgccgg aagctgcggg ccctgcacct 1500 gggcaacaac gtgctgcagtcactgccctc cagggtgggc gagctgacca 1550 acctgacgca gatcgagctg cggggcaaccggctggagtg cctgcctgtg 1600 gagctgggcg agtgcccact gctcaagcgc agcggcttggtggtggagga 1650 ggacctgttc aacacactgc cacccgaggt gaaggagcgg ctgtggaggg1700 ctgacaagga gcaggcctga gcgaggccgg cccagcacag caagcagcag 1750gaccgctgcc cagtcctcag gcccggaggg gcaggcctag cttctcccag 1800 aactcccggacagccaggac agcctcgcgg ctgggcagga gcctggggcc 1850 gcttgtgagt caggccagagcgagaggaca gtatctgtgg ggctggcccc 1900 ttttctccct ctgagactca cgtcccccagggcaagtgct tgtggaggag 1950 agcaagtctc aagagcgcag tatttggata atcagggtctcctccctgga 2000 ggccagctct gccccagggg ctgagctgcc accagaggtc ctgggaccct2050 cactttagtt cttggtattt atttttctcc atctcccacc tccttcatcc 2100agataactta tacattccca agaaagttca gcccagatgg aaggtgttca 2150 gggaaaggtgggctgccttt tccccttgtc cttatttagc gatgccgccg 2200 ggcatttaac acccacctggacttcagcag agtggtccgg ggcgaaccag 2250 ccatgggacg gtcacccagc agtgccgggctgggctctgc ggtgcggtcc 2300 acgggagagc aggcctccag ctggaaaggc caggcctggagcttgcctct 2350 tcagtttttg tggcagtttt agttttttgt tttttttttt tttaatcaaa2400 aaacaatttt ttttaaaaaa aagctttgaa aatggatggt ttgggtatta 2450aaaagaaaaa aaaaacttaa aaaaaaaaag acactaacgg ccagtgagtt 2500 ggagtctcagggcagggtgg cagtttccct tgagcaaagc agccagacgt 2550 tgaactgtgt ttcctttccctgggcgcagg gtgcagggtg tcttccggat 2600 ctggtgtgac cttggtccag gagttctatttgttcctggg gagggaggtt 2650 tttttgtttg ttttttgggt ttttttggtg tcttgttttctttctcctcc 2700 atgtgtcttg gcaggcactc atttctgtgg ctgtcggcca gagggaatgt2750 tctggagctg ccaaggaggg aggagactcg ggttggctaa tccccggatg 2800aacggtgctc cattcgcacc tcccctcctc gtgcctgccc tgcctctcca 2850 cgcacagtgttaaggagcca agaggagcca cttcgcccag actttgtttc 2900 cccacctcct gcggcatgggtgtgtccagt gccaccgctg gcctccgctg 2950 cttccatcag ccctgtcgcc acctggtccttcatgaagag cagacactta 3000 gaggctggtc gggaatgggg aggtcgcccc tgggagggcaggcgttggtt 3050 ccaagccggt tcccgtccct ggcgcctgga gtgcacacag cccagtcggc3100 acctggtggc tggaagccaa cctgctttag atcactcggg tccccacctt 3150agaagggtcc ccgccttaga tcaatcacgt ggacactaag gcacgtttta 3200 gagtctcttgtcttaatgat tatgtccatc cgtctgtccg tccatttgtg 3250 ttttctgcgt cgtgtcattggatataatcc tcagaaataa tgcacactag 3300 cctctgacaa ccatgaagca aaaatccgttacatgtgggt ctgaacttgt 3350 agactcggtc acagtatcaa ataaaatcta taacagaaaaaaaaaaaaaa 3400 a 3401 250 546 PRT Homo Sapien 250 Met Arg Gln Thr IleIle Lys Val Ile Lys Phe Ile Leu Ile Ile 1 5 10 15 Cys Tyr Thr Val TyrTyr Val His Asn Ile Lys Phe Asp Val Asp 20 25 30 Cys Thr Val Asp Ile GluSer Leu Thr Gly Tyr Arg Thr Tyr Arg 35 40 45 Cys Ala His Pro Leu Ala ThrLeu Phe Lys Ile Leu Ala Ser Phe 50 55 60 Tyr Ile Ser Leu Val Ile Phe TyrGly Leu Ile Cys Met Tyr Thr 65 70 75 Leu Trp Trp Met Leu Arg Arg Ser LeuLys Lys Tyr Ser Phe Glu 80 85 90 Ser Ile Arg Glu Glu Ser Ser Tyr Ser AspIle Pro Asp Val Lys 95 100 105 Asn Asp Phe Ala Phe Met Leu His Leu IleAsp Gln Tyr Asp Pro 110 115 120 Leu Tyr Ser Lys Arg Phe Ala Val Phe LeuSer Glu Val Ser Glu 125 130 135 Asn Lys Leu Arg Gln Leu Asn Leu Asn AsnGlu Trp Thr Leu Asp 140 145 150 Lys Leu Arg Gln Arg Leu Thr Lys Asn AlaGln Asp Lys Leu Glu 155 160 165 Leu His Leu Phe Met Leu Ser Gly Ile ProAsp Thr Val Phe Asp 170 175 180 Leu Val Glu Leu Glu Val Leu Lys Leu GluLeu Ile Pro Asp Val 185 190 195 Thr Ile Pro Pro Ser Ile Ala Gln Leu ThrGly Leu Lys Glu Leu 200 205 210 Trp Leu Tyr His Thr Ala Ala Lys Ile GluAla Pro Ala Leu Ala 215 220 225 Phe Leu Arg Glu Asn Leu Arg Ala Leu HisIle Lys Phe Thr Asp 230 235 240 Ile Lys Glu Ile Pro Leu Trp Ile Tyr SerLeu Lys Thr Leu Glu 245 250 255 Glu Leu His Leu Thr Gly Asn Leu Ser AlaGlu Asn Asn Arg Tyr 260 265 270 Ile Val Ile Asp Gly Leu Arg Glu Leu LysArg Leu Lys Val Leu 275 280 285 Arg Leu Lys Ser Asn Leu Ser Lys Leu ProGln Val Val Thr Asp 290 295 300 Val Gly Val His Leu Gln Lys Leu Ser IleAsn Asn Glu Gly Thr 305 310 315 Lys Leu Ile Val Leu Asn Ser Leu Lys LysMet Ala Asn Leu Thr 320 325 330 Glu Leu Glu Leu Ile Arg Cys Asp Leu GluArg Ile Pro His Ser 335 340 345 Ile Phe Ser Leu His Asn Leu Gln Glu IleAsp Leu Lys Asp Asn 350 355 360 Asn Leu Lys Thr Ile Glu Glu Ile Ile SerPhe Gln His Leu His 365 370 375 Arg Leu Thr Cys Leu Lys Leu Trp Tyr AsnHis Ile Ala Tyr Ile 380 385 390 Pro Ile Gln Ile Gly Asn Leu Thr Asn LeuGlu Arg Leu Tyr Leu 395 400 405 Asn Arg Asn Lys Ile Glu Lys Ile Pro ThrGln Leu Phe Tyr Cys 410 415 420 Arg Lys Leu Arg Tyr Leu Asp Leu Ser HisAsn Asn Leu Thr Phe 425 430 435 Leu Pro Ala Asp Ile Gly Leu Leu Gln AsnLeu Gln Asn Leu Ala 440 445 450 Ile Thr Ala Asn Arg Ile Glu Thr Leu ProPro Glu Leu Phe Gln 455 460 465 Cys Arg Lys Leu Arg Ala Leu His Leu GlyAsn Asn Val Leu Gln 470 475 480 Ser Leu Pro Ser Arg Val Gly Glu Leu ThrAsn Leu Thr Gln Ile 485 490 495 Glu Leu Arg Gly Asn Arg Leu Glu Cys LeuPro Val Glu Leu Gly 500 505 510 Glu Cys Pro Leu Leu Lys Arg Ser Gly LeuVal Val Glu Glu Asp 515 520 525 Leu Phe Asn Thr Leu Pro Pro Glu Val LysGlu Arg Leu Trp Arg 530 535 540 Ala Asp Lys Glu Gln Ala 545 251 20 DNAArtificial Sequence Synthetic Oligonucleotide Probe 251 caacaatgagggcaccaagc 20 252 24 DNA Artificial Sequence Synthetic OligonucleotideProbe 252 gatggctagg ttctggaggt tctg 24 253 47 DNA Artificial SequenceSynthetic Oligonucleotide Probe 253 caacctgcag gagattgacc tcaaggacaacaacctcaag accatcg 47 254 1650 DNA Homo Sapien 254 gcctgttgct gatgctgccgtgcggtactt gtcatggagc tggcactgcg 50 gcgctctccc gtcccgcggt ggttgctgctgctgccgctg ctgctgggcc 100 tgaacgcagg agctgtcatt gactggccca cagaggagggcaaggaagta 150 tgggattatg tgacggtccg caaggatgcc tacatgttct ggtggctcta200 ttatgccacc aactcctgca agaacttctc agaactgccc ctggtcatgt 250ggcttcaggg cggtccaggc ggttctagca ctggatttgg aaactttgag 300 gaaattgggccccttgacag tgatctcaaa ccacggaaaa ccacctggct 350 ccaggctgcc agtctcctatttgtggataa tcccgtgggc actgggttca 400 gttatgtgaa tggtagtggt gcctatgccaaggacctggc tatggtggct 450 tcagacatga tggttctcct gaagaccttc ttcagttgccacaaagaatt 500 ccagacagtt ccattctaca ttttctcaga gtcctatgga ggaaaaatgg550 cagctggcat tggtctagag ctttataagg ccattcagcg agggaccatc 600aagtgcaact ttgcgggggt tgccttgggt gattcctgga tctcccctgt 650 tgattcggtgctctcctggg gaccttacct gtacagcatg tctcttctcg 700 aagacaaagg tctggcagaggtgtctaagg ttgcagagca agtactgaat 750 gccgtaaata aggggctcta cagagaggccacagagctgt gggggaaagc 800 agaaatgatc attgaacaga acacagatgg ggtgaacttctataacatct 850 taactaaaag cactcccacg tctacaatgg agtcgagtct agaattcaca900 cagagccacc tagtttgtct ttgtcagcgc cacgtgagac acctacaacg 950agatgcctta agccagctca tgaatggccc catcagaaag aagctcaaaa 1000 ttattcctgaggatcaatcc tggggaggcc aggctaccaa cgtctttgtg 1050 aacatggagg aggacttcatgaagccagtc attagcattg tggacgagtt 1100 gctggaggca gggatcaacg tgacggtgtataatggacag ctggatctca 1150 tcgtagatac catgggtcag gaggcctggg tgcggaaactgaagtggcca 1200 gaactgccta aattcagtca gctgaagtgg aaggccctgt acagtgaccc1250 taaatctttg gaaacatctg cttttgtcaa gtcctacaag aaccttgctt 1300tctactggat tctgaaagct ggtcatatgg ttccttctga ccaaggggac 1350 atggctctgaagatgatgag actggtgact cagcaagaat aggatggatg 1400 gggctggaga tgagctggtttggccttggg gcacagagct gagctgaggc 1450 cgctgaagct gtaggaagcg ccattcttccctgtatctaa ctggggctgt 1500 gatcaagaag gttctgacca gcttctgcag aggataaaatcattgtctct 1550 ggaggcaatt tggaaattat ttctgcttct taaaaaaacc taagattttt1600 taaaaaattg atttgttttg atcaaaataa aggatgataa tagatattaa 1650 255 452PRT Homo Sapien 255 Met Glu Leu Ala Leu Arg Arg Ser Pro Val Pro Arg TrpLeu Leu 1 5 10 15 Leu Leu Pro Leu Leu Leu Gly Leu Asn Ala Gly Ala ValIle Asp 20 25 30 Trp Pro Thr Glu Glu Gly Lys Glu Val Trp Asp Tyr Val ThrVal 35 40 45 Arg Lys Asp Ala Tyr Met Phe Trp Trp Leu Tyr Tyr Ala Thr Asn50 55 60 Ser Cys Lys Asn Phe Ser Glu Leu Pro Leu Val Met Trp Leu Gln 6570 75 Gly Gly Pro Gly Gly Ser Ser Thr Gly Phe Gly Asn Phe Glu Glu 80 8590 Ile Gly Pro Leu Asp Ser Asp Leu Lys Pro Arg Lys Thr Thr Trp 95 100105 Leu Gln Ala Ala Ser Leu Leu Phe Val Asp Asn Pro Val Gly Thr 110 115120 Gly Phe Ser Tyr Val Asn Gly Ser Gly Ala Tyr Ala Lys Asp Leu 125 130135 Ala Met Val Ala Ser Asp Met Met Val Leu Leu Lys Thr Phe Phe 140 145150 Ser Cys His Lys Glu Phe Gln Thr Val Pro Phe Tyr Ile Phe Ser 155 160165 Glu Ser Tyr Gly Gly Lys Met Ala Ala Gly Ile Gly Leu Glu Leu 170 175180 Tyr Lys Ala Ile Gln Arg Gly Thr Ile Lys Cys Asn Phe Ala Gly 185 190195 Val Ala Leu Gly Asp Ser Trp Ile Ser Pro Val Asp Ser Val Leu 200 205210 Ser Trp Gly Pro Tyr Leu Tyr Ser Met Ser Leu Leu Glu Asp Lys 215 220225 Gly Leu Ala Glu Val Ser Lys Val Ala Glu Gln Val Leu Asn Ala 230 235240 Val Asn Lys Gly Leu Tyr Arg Glu Ala Thr Glu Leu Trp Gly Lys 245 250255 Ala Glu Met Ile Ile Glu Gln Asn Thr Asp Gly Val Asn Phe Tyr 260 265270 Asn Ile Leu Thr Lys Ser Thr Pro Thr Ser Thr Met Glu Ser Ser 275 280285 Leu Glu Phe Thr Gln Ser His Leu Val Cys Leu Cys Gln Arg His 290 295300 Val Arg His Leu Gln Arg Asp Ala Leu Ser Gln Leu Met Asn Gly 305 310315 Pro Ile Arg Lys Lys Leu Lys Ile Ile Pro Glu Asp Gln Ser Trp 320 325330 Gly Gly Gln Ala Thr Asn Val Phe Val Asn Met Glu Glu Asp Phe 335 340345 Met Lys Pro Val Ile Ser Ile Val Asp Glu Leu Leu Glu Ala Gly 350 355360 Ile Asn Val Thr Val Tyr Asn Gly Gln Leu Asp Leu Ile Val Asp 365 370375 Thr Met Gly Gln Glu Ala Trp Val Arg Lys Leu Lys Trp Pro Glu 380 385390 Leu Pro Lys Phe Ser Gln Leu Lys Trp Lys Ala Leu Tyr Ser Asp 395 400405 Pro Lys Ser Leu Glu Thr Ser Ala Phe Val Lys Ser Tyr Lys Asn 410 415420 Leu Ala Phe Tyr Trp Ile Leu Lys Ala Gly His Met Val Pro Ser 425 430435 Asp Gln Gly Asp Met Ala Leu Lys Met Met Arg Leu Val Thr Gln 440 445450 Gln Glu 256 1100 DNA Homo Sapien 256 ggccgcggga gaggaggccatgggcgcgcg cggggcgctg ctgctggcgc 50 tgctgctggc tcgggctgga ctcaggaagccggagtcgca ggaggcggcg 100 ccgttatcag gaccatgcgg ccgacgggtc atcacgtcgcgcatcgtggg 150 tggagaggac gccgaactcg ggcgttggcc gtggcagggg agcctgcgcc200 tgtgggattc ccacgtatgc ggagtgagcc tgctcagcca ccgctgggca 250ctcacggcgg cgcactgctt tgaaacctat agtgacctta gtgatccctc 300 cgggtggatggtccagtttg gccagctgac ttccatgcca tccttctgga 350 gcctgcaggc ctactacacccgttacttcg tatcgaatat ctatctgagc 400 cctcgctacc tggggaattc accctatgacattgccttgg tgaagctgtc 450 tgcacctgtc acctacacta aacacatcca gcccatctgtctccaggcct 500 ccacatttga gtttgagaac cggacagact gctgggtgac tggctggggg550 tacatcaaag aggatgaggc actgccatct ccccacaccc tccaggaagt 600tcaggtcgcc atcataaaca actctatgtg caaccacctc ttcctcaagt 650 acagtttccgcaaggacatc tttggagaca tggtttgtgc tggcaacgcc 700 caaggcggga aggatgcctgcttcggtgac tcaggtggac ccttggcctg 750 taacaagaat ggactgtggt atcagattggagtcgtgagc tggggagtgg 800 gctgtggtcg gcccaatcgg cccggtgtct acaccaatatcagccaccac 850 tttgagtgga tccagaagct gatggcccag agtggcatgt cccagccaga900 cccctcctgg ccactactct ttttccctct tctctgggct ctcccactcc 950tggggccggt ctgagcctac ctgagcccat gcagcctggg gccactgcca 1000 agtcaggccctggttctctt ctgtcttgtt tggtaataaa cacattccag 1050 ttgatgcctt gcagggcattcttcaaaaaa aaaaaaaaaa aaaaaaaaaa 1100 257 314 PRT Homo Sapien 257 MetGly Ala Arg Gly Ala Leu Leu Leu Ala Leu Leu Leu Ala Arg 1 5 10 15 AlaGly Leu Arg Lys Pro Glu Ser Gln Glu Ala Ala Pro Leu Ser 20 25 30 Gly ProCys Gly Arg Arg Val Ile Thr Ser Arg Ile Val Gly Gly 35 40 45 Glu Asp AlaGlu Leu Gly Arg Trp Pro Trp Gln Gly Ser Leu Arg 50 55 60 Leu Trp Asp SerHis Val Cys Gly Val Ser Leu Leu Ser His Arg 65 70 75 Trp Ala Leu Thr AlaAla His Cys Phe Glu Thr Tyr Ser Asp Leu 80 85 90 Ser Asp Pro Ser Gly TrpMet Val Gln Phe Gly Gln Leu Thr Ser 95 100 105 Met Pro Ser Phe Trp SerLeu Gln Ala Tyr Tyr Thr Arg Tyr Phe 110 115 120 Val Ser Asn Ile Tyr LeuSer Pro Arg Tyr Leu Gly Asn Ser Pro 125 130 135 Tyr Asp Ile Ala Leu ValLys Leu Ser Ala Pro Val Thr Tyr Thr 140 145 150 Lys His Ile Gln Pro IleCys Leu Gln Ala Ser Thr Phe Glu Phe 155 160 165 Glu Asn Arg Thr Asp CysTrp Val Thr Gly Trp Gly Tyr Ile Lys 170 175 180 Glu Asp Glu Ala Leu ProSer Pro His Thr Leu Gln Glu Val Gln 185 190 195 Val Ala Ile Ile Asn AsnSer Met Cys Asn His Leu Phe Leu Lys 200 205 210 Tyr Ser Phe Arg Lys AspIle Phe Gly Asp Met Val Cys Ala Gly 215 220 225 Asn Ala Gln Gly Gly LysAsp Ala Cys Phe Gly Asp Ser Gly Gly 230 235 240 Pro Leu Ala Cys Asn LysAsn Gly Leu Trp Tyr Gln Ile Gly Val 245 250 255 Val Ser Trp Gly Val GlyCys Gly Arg Pro Asn Arg Pro Gly Val 260 265 270 Tyr Thr Asn Ile Ser HisHis Phe Glu Trp Ile Gln Lys Leu Met 275 280 285 Ala Gln Ser Gly Met SerGln Pro Asp Pro Ser Trp Pro Leu Leu 290 295 300 Phe Phe Pro Leu Leu TrpAla Leu Pro Leu Leu Gly Pro Val 305 310 258 2427 DNA Homo Sapien 258cccacgcgtc cgcggacgcg tgggaagggc agaatgggac tccaagcctg 50 cctcctagggctctttgccc tcatcctctc tggcaaatgc agttacagcc 100 cggagcccga ccagcggaggacgctgcccc caggctgggt gtccctgggc 150 cgtgcggacc ctgaggaaga gctgagtctcacctttgccc tgagacagca 200 gaatgtggaa agactctcgg agctggtgca ggctgtgtcggatcccagct 250 ctcctcaata cggaaaatac ctgaccctag agaatgtggc tgatctggtg300 aggccatccc cactgaccct ccacacggtg caaaaatggc tcttggcagc 350cggagcccag aagtgccatt ctgtgatcac acaggacttt ctgacttgct 400 ggctgagcatccgacaagca gagctgctgc tccctggggc tgagtttcat 450 cactatgtgg gaggacctacggaaacccat gttgtaaggt ccccacatcc 500 ctaccagctt ccacaggcct tggccccccatgtggacttt gtggggggac 550 tgcaccgttt tcccccaaca tcatccctga ggcaacgtcctgagccgcag 600 gtgacaggga ctgtaggcct gcatctgggg gtaaccccct ctgtgatccg650 taagcgatac aacttgacct cacaagacgt gggctctggc accagcaata 700acagccaagc ctgtgcccag ttcctggagc agtatttcca tgactcagac 750 ctggctcagttcatgcgcct cttcggtggc aactttgcac atcaggcatc 800 agtagcccgt gtggttggacaacagggccg gggccgggcc gggattgagg 850 ccagtctaga tgtgcagtac ctgatgagtgctggtgccaa catctccacc 900 tgggtctaca gtagccctgg ccggcatgag ggacaggagcccttcctgca 950 gtggctcatg ctgctcagta atgagtcagc cctgccacat gtgcatactg1000 tgagctatgg agatgatgag gactccctca gcagcgccta catccagcgg 1050gtcaacactg agctcatgaa ggctgccgct cggggtctca ccctgctctt 1100 cgcctcaggtgacagtgggg ccgggtgttg gtctgtctct ggaagacacc 1150 agttccgccc taccttccctgcctccagcc cctatgtcac cacagtggga 1200 ggcacatcct tccaggaacc tttcctcatcacaaatgaaa ttgttgacta 1250 tatcagtggt ggtggcttca gcaatgtgtt cccacggccttcataccagg 1300 aggaagctgt aacgaagttc ctgagctcta gcccccacct gccaccatcc1350 agttacttca atgccagtgg ccgtgcctac ccagatgtgg ctgcactttc 1400tgatggctac tgggtggtca gcaacagagt gcccattcca tgggtgtccg 1450 gaacctcggcctctactcca gtgtttgggg ggatcctatc cttgatcaat 1500 gagcacagga tccttagtggccgcccccct cttggctttc tcaacccaag 1550 gctctaccag cagcatgggg caggtctctttgatgtaacc cgtggctgcc 1600 atgagtcctg tctggatgaa gaggtagagg gccagggtttctgctctggt 1650 cctggctggg atcctgtaac aggctgggga acaccaactt cccagctttg1700 ctgaagactc tactcaaccc ctgacccttt cctatcagga gagatggctt 1750gtcccctgcc ctgaagctgg cagttcagtc ccttattctg ccctgttgga 1800 agccctgctgaaccctcaac tattgactgc tgcagacagc ttatctccct 1850 aaccctgaaa tgctgtgagcttgacttgac tcccaaccct accatgctcc 1900 atcatactca ggtctcccta ctcctgccttagattcctca ataagatgct 1950 gtaactagca ttttttgaat gcctctccct ccgcatctcatctttctctt 2000 ttcaatcagg cttttccaaa gggttgtata cagactctgt gcactatttc2050 acttgatatt cattccccaa ttcactgcaa ggagacctct actgtcaccg 2100tttactcttt cctaccctga catccagaaa caatggcctc cagtgcatac 2150 ttctcaatctttgctttatg gcctttccat catagttgcc cactccctct 2200 ccttacttag cttccaggtcttaacttctc tgactactct tgtcttcctc 2250 tctcatcaat ttctgcttct tcatggaatgctgaccttca ttgctccatt 2300 tgtagatttt tgctcttctc agtttactca ttgtcccctggaacaaatca 2350 ctgacatcta caaccattac catctcacta aataagactt tctatccaat2400 aatgattgat acctcaaatg taaaaaa 2427 259 556 PRT Homo Sapien 259 MetGly Leu Gln Ala Cys Leu Leu Gly Leu Phe Ala Leu Ile Leu 1 5 10 15 SerGly Lys Cys Ser Tyr Ser Pro Glu Pro Asp Gln Arg Arg Thr 20 25 30 Leu ProPro Gly Trp Val Ser Leu Gly Arg Ala Asp Pro Glu Glu 35 40 45 Glu Leu SerLeu Thr Phe Ala Leu Arg Gln Gln Asn Val Glu Arg 50 55 60 Leu Ser Glu LeuVal Gln Ala Val Ser Asp Pro Ser Ser Pro Gln 65 70 75 Tyr Gly Lys Tyr LeuThr Leu Glu Asn Val Ala Asp Leu Val Arg 80 85 90 Pro Ser Pro Leu Thr LeuHis Thr Val Gln Lys Trp Leu Leu Ala 95 100 105 Ala Gly Ala Gln Lys CysHis Ser Val Ile Thr Gln Asp Phe Leu 110 115 120 Thr Cys Trp Leu Ser IleArg Gln Ala Glu Leu Leu Leu Pro Gly 125 130 135 Ala Glu Phe His His TyrVal Gly Gly Pro Thr Glu Thr His Val 140 145 150 Val Arg Ser Pro His ProTyr Gln Leu Pro Gln Ala Leu Ala Pro 155 160 165 His Val Asp Phe Val GlyGly Leu His Arg Phe Pro Pro Thr Ser 170 175 180 Ser Leu Arg Gln Arg ProGlu Pro Gln Val Thr Gly Thr Val Gly 185 190 195 Leu His Leu Gly Val ThrPro Ser Val Ile Arg Lys Arg Tyr Asn 200 205 210 Leu Thr Ser Gln Asp ValGly Ser Gly Thr Ser Asn Asn Ser Gln 215 220 225 Ala Cys Ala Gln Phe LeuGlu Gln Tyr Phe His Asp Ser Asp Leu 230 235 240 Ala Gln Phe Met Arg LeuPhe Gly Gly Asn Phe Ala His Gln Ala 245 250 255 Ser Val Ala Arg Val ValGly Gln Gln Gly Arg Gly Arg Ala Gly 260 265 270 Ile Glu Ala Ser Leu AspVal Gln Tyr Leu Met Ser Ala Gly Ala 275 280 285 Asn Ile Ser Thr Trp ValTyr Ser Ser Pro Gly Arg His Glu Gly 290 295 300 Gln Glu Pro Phe Leu GlnTrp Leu Met Leu Leu Ser Asn Glu Ser 305 310 315 Ala Leu Pro His Val HisThr Val Ser Tyr Gly Asp Asp Glu Asp 320 325 330 Ser Leu Ser Ser Ala TyrIle Gln Arg Val Asn Thr Glu Leu Met 335 340 345 Lys Ala Ala Ala Arg GlyLeu Thr Leu Leu Phe Ala Ser Gly Asp 350 355 360 Ser Gly Ala Gly Cys TrpSer Val Ser Gly Arg His Gln Phe Arg 365 370 375 Pro Thr Phe Pro Ala SerSer Pro Tyr Val Thr Thr Val Gly Gly 380 385 390 Thr Ser Phe Gln Glu ProPhe Leu Ile Thr Asn Glu Ile Val Asp 395 400 405 Tyr Ile Ser Gly Gly GlyPhe Ser Asn Val Phe Pro Arg Pro Ser 410 415 420 Tyr Gln Glu Glu Ala ValThr Lys Phe Leu Ser Ser Ser Pro His 425 430 435 Leu Pro Pro Ser Ser TyrPhe Asn Ala Ser Gly Arg Ala Tyr Pro 440 445 450 Asp Val Ala Ala Leu SerAsp Gly Tyr Trp Val Val Ser Asn Arg 455 460 465 Val Pro Ile Pro Trp ValSer Gly Thr Ser Ala Ser Thr Pro Val 470 475 480 Phe Gly Gly Ile Leu SerLeu Ile Asn Glu His Arg Ile Leu Ser 485 490 495 Gly Arg Pro Pro Leu GlyPhe Leu Asn Pro Arg Leu Tyr Gln Gln 500 505 510 His Gly Ala Gly Leu PheAsp Val Thr Arg Gly Cys His Glu Ser 515 520 525 Cys Leu Asp Glu Glu ValGlu Gly Gln Gly Phe Cys Ser Gly Pro 530 535 540 Gly Trp Asp Pro Val ThrGly Trp Gly Thr Pro Thr Ser Gln Leu 545 550 555 Cys 260 1638 DNA HomoSapien 260 gccgcgcgct ctctcccggc gcccacacct gtctgagcgg cgcagcgagc 50cgcggcccgg gcgggctgct cggcgcggaa cagtgctcgg catggcaggg 100 attccagggctcctcttcct tctcttcttt ctgctctgtg ctgttgggca 150 agtgagccct tacagtgccccctggaaacc cacttggcct gcataccgcc 200 tccctgtcgt cttgccccag tctaccctcaatttagccaa gccagacttt 250 ggagccgaag ccaaattaga agtatcttct tcatgtggaccccagtgtca 300 taagggaact ccactgccca cttacgaaga ggccaagcaa tatctgtctt350 atgaaacgct ctatgccaat ggcagccgca cagagacgca ggtgggcatc 400tacatcctca gcagtagtgg agatggggcc caacaccgag actcagggtc 450 ttcaggaaagtctcgaagga agcggcagat ttatggctat gacagcaggt 500 tcagcatttt tgggaaggacttcctgctca actacccttt ctcaacatca 550 gtgaagttat ccacgggctg caccggcaccctggtggcag agaagcatgt 600 cctcacagct gcccactgca tacacgatgg aaaaacctatgtgaaaggaa 650 cccagaagct tcgagtgggc ttcctaaagc ccaagtttaa agatggtggt700 cgaggggcca acgactccac ttcagccatg cccgagcaga tgaaatttca 750gtggatccgg gtgaaacgca cccatgtgcc caagggttgg atcaagggca 800 atgccaatgacatcggcatg gattatgatt atgccctcct ggaactcaaa 850 aagccccaca agagaaaatttatgaagatt ggggtgagcc ctcctgctaa 900 gcagctgcca gggggcagaa ttcacttctctggttatgac aatgaccgac 950 caggcaattt ggtgtatcgc ttctgtgacg tcaaagacgagacctatgac 1000 ttgctctacc agcaatgcga tgcccagcca ggggccagcg ggtctggggt1050 ctatgtgagg atgtggaaga gacagcagca gaagtgggag cgaaaaatta 1100ttggcatttt ttcagggcac cagtgggtgg acatgaatgg ttccccacag 1150 gatttcaacgtggctgtcag aatcactcct ctcaaatatg cccagatttg 1200 ctattggatt aaaggaaactacctggattg tagggagggg tgacacagtg 1250 ttccctcctg gcagcaatta agggtcttcatgttcttatt ttaggagagg 1300 ccaaattgtt ttttgtcatt ggcgtgcaca cgtgtgtgtgtgtgtgtgtg 1350 tgtgtgtaag gtgtcttata atcttttacc tatttcttac aattgcaaga1400 tgactggctt tactatttga aaactggttt gtgtatcata tcatatatca 1450tttaagcagt ttgaaggcat acttttgcat agaaataaaa aaaatactga 1500 tttggggcaatgaggaatat ttgacaatta agttaatctt cacgtttttg 1550 caaactttga tttttatttcatctgaactt gtttcaaaga tttatattaa 1600 atatttggca tacaagagat atgaaaaaaaaaaaaaaa 1638 261 383 PRT Homo Sapien 261 Met Ala Gly Ile Pro Gly LeuLeu Phe Leu Leu Phe Phe Leu Leu 1 5 10 15 Cys Ala Val Gly Gln Val SerPro Tyr Ser Ala Pro Trp Lys Pro 20 25 30 Thr Trp Pro Ala Tyr Arg Leu ProVal Val Leu Pro Gln Ser Thr 35 40 45 Leu Asn Leu Ala Lys Pro Asp Phe GlyAla Glu Ala Lys Leu Glu 50 55 60 Val Ser Ser Ser Cys Gly Pro Gln Cys HisLys Gly Thr Pro Leu 65 70 75 Pro Thr Tyr Glu Glu Ala Lys Gln Tyr Leu SerTyr Glu Thr Leu 80 85 90 Tyr Ala Asn Gly Ser Arg Thr Glu Thr Gln Val GlyIle Tyr Ile 95 100 105 Leu Ser Ser Ser Gly Asp Gly Ala Gln His Arg AspSer Gly Ser 110 115 120 Ser Gly Lys Ser Arg Arg Lys Arg Gln Ile Tyr GlyTyr Asp Ser 125 130 135 Arg Phe Ser Ile Phe Gly Lys Asp Phe Leu Leu AsnTyr Pro Phe 140 145 150 Ser Thr Ser Val Lys Leu Ser Thr Gly Cys Thr GlyThr Leu Val 155 160 165 Ala Glu Lys His Val Leu Thr Ala Ala His Cys IleHis Asp Gly 170 175 180 Lys Thr Tyr Val Lys Gly Thr Gln Lys Leu Arg ValGly Phe Leu 185 190 195 Lys Pro Lys Phe Lys Asp Gly Gly Arg Gly Ala AsnAsp Ser Thr 200 205 210 Ser Ala Met Pro Glu Gln Met Lys Phe Gln Trp IleArg Val Lys 215 220 225 Arg Thr His Val Pro Lys Gly Trp Ile Lys Gly AsnAla Asn Asp 230 235 240 Ile Gly Met Asp Tyr Asp Tyr Ala Leu Leu Glu LeuLys Lys Pro 245 250 255 His Lys Arg Lys Phe Met Lys Ile Gly Val Ser ProPro Ala Lys 260 265 270 Gln Leu Pro Gly Gly Arg Ile His Phe Ser Gly TyrAsp Asn Asp 275 280 285 Arg Pro Gly Asn Leu Val Tyr Arg Phe Cys Asp ValLys Asp Glu 290 295 300 Thr Tyr Asp Leu Leu Tyr Gln Gln Cys Asp Ala GlnPro Gly Ala 305 310 315 Ser Gly Ser Gly Val Tyr Val Arg Met Trp Lys ArgGln Gln Gln 320 325 330 Lys Trp Glu Arg Lys Ile Ile Gly Ile Phe Ser GlyHis Gln Trp 335 340 345 Val Asp Met Asn Gly Ser Pro Gln Asp Phe Asn ValAla Val Arg 350 355 360 Ile Thr Pro Leu Lys Tyr Ala Gln Ile Cys Tyr TrpIle Lys Gly 365 370 375 Asn Tyr Leu Asp Cys Arg Glu Gly 380 262 1378 DNAHomo Sapien 262 gcatcgccct gggtctctcg agcctgctgc ctgctccccc gccccaccag50 ccatggtggt ttctggagcg cccccagccc tgggtggggg ctgtctcggc 100 accttcacctccctgctgct gctggcgtcg acagccatcc tcaatgcggc 150 caggatacct gttcccccagcctgtgggaa gccccagcag ctgaaccggg 200 ttgtgggcgg cgaggacagc actgacagcgagtggccctg gatcgtgagc 250 atccagaaga atgggaccca ccactgcgca ggttctctgctcaccagccg 300 ctgggtgatc actgctgccc actgtttcaa ggacaacctg aacaaaccat350 acctgttctc tgtgctgctg ggggcctggc agctggggaa ccctggctct 400cggtcccaga aggtgggtgt tgcctgggtg gagccccacc ctgtgtattc 450 ctggaaggaaggtgcctgtg cagacattgc cctggtgcgt ctcgagcgct 500 ccatacagtt ctcagagcgggtcctgccca tctgcctacc tgatgcctct 550 atccacctcc ctccaaacac ccactgctggatctcaggct gggggagcat 600 ccaagatgga gttcccttgc cccaccctca gaccctgcagaagctgaagg 650 ttcctatcat cgactcggaa gtctgcagcc atctgtactg gcggggagca700 ggacagggac ccatcactga ggacatgctg tgtgccggct acttggaggg 750ggagcgggat gcttgtctgg gcgactccgg gggccccctc atgtgccagg 800 tggacggcgcctggctgctg gccggcatca tcagctgggg cgagggctgt 850 gccgagcgca acaggcccggggtctacatc agcctctctg cgcaccgctc 900 ctgggtggag aagatcgtgc aaggggtgcagctccgcggg cgcgctcagg 950 ggggtggggc cctcagggca ccgagccagg gctctggggccgccgcgcgc 1000 tcctagggcg cagcgggacg cggggctcgg atctgaaagg cggccagatc1050 cacatctgga tctggatctg cggcggcctc gggcggtttc ccccgccgta 1100aataggctca tctacctcta cctctggggg cccggacggc tgctgcggaa 1150 aggaaaccccctccccgacc cgcccgacgg cctcaggccc ccctccaagg 1200 catcaggccc cgcccaacggcctcatgtcc ccgcccccac gacttccggc 1250 cccgcccccg ggccccagcg cttttgtgtatataaatgtt aatgattttt 1300 ataggtattt gtaaccctgc ccacatatct tatttattcctccaatttca 1350 ataaattatt tattctccaa aaaaaaaa 1378 263 317 PRT HomoSapien 263 Met Val Val Ser Gly Ala Pro Pro Ala Leu Gly Gly Gly Cys Leu 15 10 15 Gly Thr Phe Thr Ser Leu Leu Leu Leu Ala Ser Thr Ala Ile Leu 2025 30 Asn Ala Ala Arg Ile Pro Val Pro Pro Ala Cys Gly Lys Pro Gln 35 4045 Gln Leu Asn Arg Val Val Gly Gly Glu Asp Ser Thr Asp Ser Glu 50 55 60Trp Pro Trp Ile Val Ser Ile Gln Lys Asn Gly Thr His His Cys 65 70 75 AlaGly Ser Leu Leu Thr Ser Arg Trp Val Ile Thr Ala Ala His 80 85 90 Cys PheLys Asp Asn Leu Asn Lys Pro Tyr Leu Phe Ser Val Leu 95 100 105 Leu GlyAla Trp Gln Leu Gly Asn Pro Gly Ser Arg Ser Gln Lys 110 115 120 Val GlyVal Ala Trp Val Glu Pro His Pro Val Tyr Ser Trp Lys 125 130 135 Glu GlyAla Cys Ala Asp Ile Ala Leu Val Arg Leu Glu Arg Ser 140 145 150 Ile GlnPhe Ser Glu Arg Val Leu Pro Ile Cys Leu Pro Asp Ala 155 160 165 Ser IleHis Leu Pro Pro Asn Thr His Cys Trp Ile Ser Gly Trp 170 175 180 Gly SerIle Gln Asp Gly Val Pro Leu Pro His Pro Gln Thr Leu 185 190 195 Gln LysLeu Lys Val Pro Ile Ile Asp Ser Glu Val Cys Ser His 200 205 210 Leu TyrTrp Arg Gly Ala Gly Gln Gly Pro Ile Thr Glu Asp Met 215 220 225 Leu CysAla Gly Tyr Leu Glu Gly Glu Arg Asp Ala Cys Leu Gly 230 235 240 Asp SerGly Gly Pro Leu Met Cys Gln Val Asp Gly Ala Trp Leu 245 250 255 Leu AlaGly Ile Ile Ser Trp Gly Glu Gly Cys Ala Glu Arg Asn 260 265 270 Arg ProGly Val Tyr Ile Ser Leu Ser Ala His Arg Ser Trp Val 275 280 285 Glu LysIle Val Gln Gly Val Gln Leu Arg Gly Arg Ala Gln Gly 290 295 300 Gly GlyAla Leu Arg Ala Pro Ser Gln Gly Ser Gly Ala Ala Ala 305 310 315 Arg Ser264 24 DNA Artificial Sequence Synthetic Oligonucleotide Probe 264gtccgcaagg atgcctacat gttc 24 265 19 DNA Artificial Sequence SyntheticOligonucleotide Probe 265 gcagaggtgt ctaaggttg 19 266 24 DNA ArtificialSequence Synthetic Oligonucleotide Probe 266 agctctagac caatgccagc ttcc24 267 45 DNA Artificial Sequence Synthetic Oligonucleotide Probe 267gccaccaact cctgcaagaa cttctcagaa ctgcccctgg tcatg 45 268 25 DNAArtificial Sequence Synthetic Oligonucleotide Probe 268 ggggaattcaccctatgaca ttgcc 25 269 24 DNA Artificial Sequence SyntheticOligonucleotide Probe 269 gaatgccctg caagcatcaa ctgg 24 270 50 DNAArtificial Sequence Synthetic Oligonucleotide Probe 270 gcacctgtcacctacactaa acacatccag cccatctgtc tccaggcctc 50 271 26 DNA ArtificialSequence Synthetic Oligonucleotide Probe 271 gcggaagggc agaatgggactccaag 26 272 18 DNA Artificial Sequence Synthetic Oligonucleotide Probe272 cagccctgcc acatgtgc 18 273 18 DNA Artificial Sequence SyntheticOligonucleotide Probe 273 tactgggtgg tcagcaac 18 274 24 DNA ArtificialSequence Synthetic Oligonucleotide Probe 274 ggcgaagagc agggtgagac cccg24 275 45 DNA Artificial Sequence Synthetic Oligonucleotide Probe 275gccctcatcc tctctggcaa atgcagttac agcccggagc ccgac 45 276 21 DNAArtificial Sequence Synthetic Oligonucleotide Probe 276 gggcagggattccagggctc c 21 277 18 DNA Artificial Sequence Synthetic OligonucleotideProbe 277 ggctatgaca gcaggttc 18 278 18 DNA Artificial SequenceSynthetic Oligonucleotide Probe 278 tgacaatgac cgaccagg 18 279 24 DNAArtificial Sequence Synthetic Oligonucleotide Probe 279 gcatcgcattgctggtagag caag 24 280 45 DNA Artificial Sequence SyntheticOligonucleotide Probe 280 ttacagtgcc ccctggaaac ccacttggcc tgcataccgcctccc 45 281 34 DNA Artificial Sequence Synthetic Oligonucleotide Probe281 cgtctcgagc gctccataca gttcccttgc ccca 34 282 61 DNA ArtificialSequence Synthetic Oligonucleotide Probe 282 tggaggggga gcgggatgcttgtctgggcg actccggggg ccccctcatg 50 tgccaggtgg a 61 283 119 DNAArtificial Sequence Synthetic Oligonucleotide Probe 283 ccctcagaccctgcagaagc tgaaggttcc tatcatcgac tcggaagtct 50 gcagccatct gtactggcggggagcaggac agggacccat cactgaggac 100 atgctgtgtg ccggctact 119 284 1875DNA Homo Sapien 284 gacggctggc caccatgcac ggctcctgca gtttcctgatgcttctgctg 50 ccgctactgc tactgctggt ggccaccaca ggccccgttg gagccctcac 100agatgaggag aaacgtttga tggtggagct gcacaacctc taccgggccc 150 aggtatccccgacggcctca gacatgctgc acatgagatg ggacgaggag 200 ctggccgcct tcgccaaggcctacgcacgg cagtgcgtgt ggggccacaa 250 caaggagcgc gggcgccgcg gcgagaatctgttcgccatc acagacgagg 300 gcatggacgt gccgctggcc atggaggagt ggcaccacgagcgtgagcac 350 tacaacctca gcgccgccac ctgcagccca ggccagatgt gcggccacta400 cacgcaggtg gtatgggcca agacagagag gatcggctgt ggttcccact 450tctgtgagaa gctccagggt gttgaggaga ccaacatcga attactggtg 500 tgcaactatgagcctccggg gaacgtgaag gggaaacggc cctaccagga 550 ggggactccg tgctcccaatgtccctctgg ctaccactgc aagaactccc 600 tctgtgaacc catcggaagc ccggaagatgctcaggattt gccttacctg 650 gtaactgagg ccccatcctt ccgggcgact gaagcatcagactctaggaa 700 aatgggtact ccttcttccc tagcaacggg gattccggct ttcttggtaa750 cagaggtctc aggctccctg gcaaccaagg ctctgcctgc tgtggaaacc 800caggccccaa cttccttagc aacgaaagac ccgccctcca tggcaacaga 850 ggctccaccttgcgtaacaa ctgaggtccc ttccattttg gcagctcaca 900 gcctgccctc cttggatgaggagccagtta ccttccccaa atcgacccat 950 gttcctatcc caaaatcagc agacaaagtgacagacaaaa caaaagtgcc 1000 ctctaggagc ccagagaact ctctggaccc caagatgtccctgacagggg 1050 caagggaact cctaccccat gcccaggagg aggctgaggc tgaggctgag1100 ttgcctcctt ccagtgaggt cttggcctca gtttttccag cccaggacaa 1150gccaggtgag ctgcaggcca cactggacca cacggggcac acctcctcca 1200 agtccctgcccaatttcccc aatacctctg ccaccgctaa tgccacgggt 1250 gggcgtgccc tggctctgcagtcgtccttg ccaggtgcag agggccctga 1300 caagcctagc gttgtgtcag ggctgaactcgggccctggt catgtgtggg 1350 gccctctcct gggactactg ctcctgcctc ctctggtgttggctggaatc 1400 ttctgaatgg gataccactc aaagggtgaa gaggtcagct gtcctcctgt1450 catcttcccc accctgtccc cagcccctaa acaagatact tcttggttaa 1500ggccctccgg aagggaaagg ctacggggca tgtgcctcat cacaccatcc 1550 atcctggaggcacaaggcct ggctggctgc gagctcagga ggccgcctga 1600 ggactgcaca ccgggcccacacctctcctg cccctccctc ctgagtcctg 1650 ggggtgggag gatttgaggg agctcactgcctacctggcc tggggctgtc 1700 tgcccacaca gcatgtgcgc tctccctgag tgcctgtgtagctggggatg 1750 gggattccta ggggcagatg aaggacaagc cccactggag tggggttctt1800 tgagtggggg aggcagggac gagggaagga aagtaactcc tgactctcca 1850ataaaaacct gtccaacctg tgaaa 1875 285 463 PRT Homo Sapien 285 Met His GlySer Cys Ser Phe Leu Met Leu Leu Leu Pro Leu Leu 1 5 10 15 Leu Leu LeuVal Ala Thr Thr Gly Pro Val Gly Ala Leu Thr Asp 20 25 30 Glu Glu Lys ArgLeu Met Val Glu Leu His Asn Leu Tyr Arg Ala 35 40 45 Gln Val Ser Pro ThrAla Ser Asp Met Leu His Met Arg Trp Asp 50 55 60 Glu Glu Leu Ala Ala PheAla Lys Ala Tyr Ala Arg Gln Cys Val 65 70 75 Trp Gly His Asn Lys Glu ArgGly Arg Arg Gly Glu Asn Leu Phe 80 85 90 Ala Ile Thr Asp Glu Gly Met AspVal Pro Leu Ala Met Glu Glu 95 100 105 Trp His His Glu Arg Glu His TyrAsn Leu Ser Ala Ala Thr Cys 110 115 120 Ser Pro Gly Gln Met Cys Gly HisTyr Thr Gln Val Val Trp Ala 125 130 135 Lys Thr Glu Arg Ile Gly Cys GlySer His Phe Cys Glu Lys Leu 140 145 150 Gln Gly Val Glu Glu Thr Asn IleGlu Leu Leu Val Cys Asn Tyr 155 160 165 Glu Pro Pro Gly Asn Val Lys GlyLys Arg Pro Tyr Gln Glu Gly 170 175 180 Thr Pro Cys Ser Gln Cys Pro SerGly Tyr His Cys Lys Asn Ser 185 190 195 Leu Cys Glu Pro Ile Gly Ser ProGlu Asp Ala Gln Asp Leu Pro 200 205 210 Tyr Leu Val Thr Glu Ala Pro SerPhe Arg Ala Thr Glu Ala Ser 215 220 225 Asp Ser Arg Lys Met Gly Thr ProSer Ser Leu Ala Thr Gly Ile 230 235 240 Pro Ala Phe Leu Val Thr Glu ValSer Gly Ser Leu Ala Thr Lys 245 250 255 Ala Leu Pro Ala Val Glu Thr GlnAla Pro Thr Ser Leu Ala Thr 260 265 270 Lys Asp Pro Pro Ser Met Ala ThrGlu Ala Pro Pro Cys Val Thr 275 280 285 Thr Glu Val Pro Ser Ile Leu AlaAla His Ser Leu Pro Ser Leu 290 295 300 Asp Glu Glu Pro Val Thr Phe ProLys Ser Thr His Val Pro Ile 305 310 315 Pro Lys Ser Ala Asp Lys Val ThrAsp Lys Thr Lys Val Pro Ser 320 325 330 Arg Ser Pro Glu Asn Ser Leu AspPro Lys Met Ser Leu Thr Gly 335 340 345 Ala Arg Glu Leu Leu Pro His AlaGln Glu Glu Ala Glu Ala Glu 350 355 360 Ala Glu Leu Pro Pro Ser Ser GluVal Leu Ala Ser Val Phe Pro 365 370 375 Ala Gln Asp Lys Pro Gly Glu LeuGln Ala Thr Leu Asp His Thr 380 385 390 Gly His Thr Ser Ser Lys Ser LeuPro Asn Phe Pro Asn Thr Ser 395 400 405 Ala Thr Ala Asn Ala Thr Gly GlyArg Ala Leu Ala Leu Gln Ser 410 415 420 Ser Leu Pro Gly Ala Glu Gly ProAsp Lys Pro Ser Val Val Ser 425 430 435 Gly Leu Asn Ser Gly Pro Gly HisVal Trp Gly Pro Leu Leu Gly 440 445 450 Leu Leu Leu Leu Pro Pro Leu ValLeu Ala Gly Ile Phe 455 460 286 19 DNA Artificial Sequence SyntheticOligonucleotide Probe 286 tcctgcagtt tcctgatgc 19 287 24 DNA ArtificialSequence Synthetic Oligonucleotide Probe 287 ctcatattgc acaccagtaa ttcg24 288 45 DNA Artificial Sequence Synthetic Oligonucleotide Probe 288atgaggagaa acgtttgatg gtggagctgc acaacctcta ccggg 45 289 3662 DNA HomoSapien 289 gtaactgaag tcaggctttt catttgggaa gccccctcaa cagaattcgg 50tcattctcca agttatggtg gacgtacttc tgttgttctc cctctgcttg 100 ctttttcacattagcagacc ggacttaagt cacaacagat tatctttcat 150 caaggcaagt tccatgagccaccttcaaag ccttcgagaa gtgaaactga 200 acaacaatga attggagacc attccaaatctgggaccagt ctcggcaaat 250 attacacttc tctccttggc tggaaacagg attgttgaaatactccctga 300 acatctgaaa gagtttcagt cccttgaaac tttggacctt agcagcaaca350 atatttcaga gctccaaact gcatttccag ccctacagct caaatatctg 400tatctcaaca gcaaccgagt cacatcaatg gaacctgggt attttgacaa 450 tttggccaacacactccttg tgttaaagct gaacaggaac cgaatctcag 500 ctatcccacc caagatgtttaaactgcccc aactgcaaca tctcgaattg 550 aaccgaaaca agattaaaaa tgtagatggactgacattcc aaggccttgg 600 tgctctgaag tctctgaaaa tgcaaagaaa tggagtaacgaaacttatgg 650 atggagcttt ttgggggctg agcaacatgg aaattttgca gctggaccat700 aacaacctaa cagagattac caaaggctgg ctttacggct tgctgatgct 750gcaggaactt catctcagcc aaaatgccat caacaggatc agccctgatg 800 cctgggagttctgccagaag ctcagtgagc tggacctaac tttcaatcac 850 ttatcaaggt tagatgattcaagcttcctt ggcctaagct tactaaatac 900 actgcacatt gggaacaaca gagtcagctacattgctgat tgtgccttcc 950 gggggctttc cagtttaaag actttggatc tgaagaacaatgaaatttcc 1000 tggactattg aagacatgaa tggtgctttc tctgggcttg acaaactgag1050 gcgactgata ctccaaggaa atcggatccg ttctattact aaaaaagcct 1100tcactggttt ggatgcattg gagcatctag acctgagtga caacgcaatc 1150 atgtctttacaaggcaatgc attttcacaa atgaagaaac tgcaacaatt 1200 gcatttaaat acatcaagccttttgtgcga ttgccagcta aaatggctcc 1250 cacagtgggt ggcggaaaac aactttcagagctttgtaaa tgccagttgt 1300 gcccatcctc agctgctaaa aggaagaagc atttttgctgttagcccaga 1350 tggctttgtg tgtgatgatt ttcccaaacc ccagatcacg gttcagccag1400 aaacacagtc ggcaataaaa ggttccaatt tgagtttcat ctgctcagct 1450gccagcagca gtgattcccc aatgactttt gcttggaaaa aagacaatga 1500 actactgcatgatgctgaaa tggaaaatta tgcacacctc cgggcccaag 1550 gtggcgaggt gatggagtataccaccatcc ttcggctgcg cgaggtggaa 1600 tttgccagtg aggggaaata tcagtgtgtcatctccaatc actttggttc 1650 atcctactct gtcaaagcca agcttacagt aaatatgcttccctcattca 1700 ccaagacccc catggatctc accatccgag ctggggccat ggcacgcttg1750 gagtgtgctg ctgtggggca cccagccccc cagatagcct ggcagaagga 1800tgggggcaca gacttcccag ctgcacggga gagacgcatg catgtgatgc 1850 ccgaggatgacgtgttcttt atcgtggatg tgaagataga ggacattggg 1900 gtatacagct gcacagctcagaacagtgca ggaagtattt cagcaaatgc 1950 aactctgact gtcctagaaa caccatcatttttgcggcca ctgttggacc 2000 gaactgtaac caagggagaa acagccgtcc tacagtgcattgctggagga 2050 agccctcccc ctaaactgaa ctggaccaaa gatgatagcc cattggtggt2100 aaccgagagg cacttttttg cagcaggcaa tcagcttctg attattgtgg 2150actcagatgt cagtgatgct gggaaataca catgtgagat gtctaacacc 2200 cttggcactgagagaggaaa cgtgcgcctc agtgtgatcc ccactccaac 2250 ctgcgactcc cctcagatgacagccccatc gttagacgat gacggatggg 2300 ccactgtggg tgtcgtgatc atagccgtggtttgctgtgt ggtgggcacg 2350 tcactcgtgt gggtggtcat catataccac acaaggcggaggaatgaaga 2400 ttgcagcatt accaacacag atgagaccaa cttgccagca gatattccta2450 gttatttgtc atctcaggga acgttagctg acaggcagga tgggtacgtg 2500tcttcagaaa gtggaagcca ccaccagttt gtcacatctt caggtgctgg 2550 atttttcttaccacaacatg acagtagtgg gacctgccat attgacaata 2600 gcagtgaagc tgatgtggaagctgccacag atctgttcct ttgtccgttt 2650 ttgggatcca caggccctat gtatttgaagggaaatgtgt atggctcaga 2700 tccttttgaa acatatcata caggttgcag tcctgacccaagaacagttt 2750 taatggacca ctatgagccc agttacataa agaaaaagga gtgctaccca2800 tgttctcatc cttcagaaga atcctgcgaa cggagcttca gtaatatatc 2850gtggccttca catgtgagga agctacttaa cactagttac tctcacaatg 2900 aaggacctggaatgaaaaat ctgtgtctaa acaagtcctc tttagatttt 2950 agtgcaaatc cagagccagcgtcggttgcc tcgagtaatt ctttcatggg 3000 tacctttgga aaagctctca ggagacctcacctagatgcc tattcaagct 3050 ttggacagcc atcagattgt cagccaagag ccttttatttgaaagctcat 3100 tcttccccag acttggactc tgggtcagag gaagatggga aagaaaggac3150 agattttcag gaagaaaatc acatttgtac ctttaaacag actttagaaa 3200actacaggac tccaaatttt cagtcttatg acttggacac atagactgaa 3250 tgagaccaaaggaaaagctt aacatactac ctcaagtgaa cttttattta 3300 aaagagagag aatcttatgttttttaaatg gagttatgaa ttttaaaagg 3350 ataaaaatgc tttatttata cagatgaaccaaaattacaa aaagttatga 3400 aaatttttat actgggaatg atgctcatat aagaatacctttttaaacta 3450 ttttttaact ttgttttatg caaaaaagta tcttacgtaa attaatgata3500 taaatcatga ttattttatg tatttttata atgccagatt tctttttatg 3550gaaaatgagt tactaaagca ttttaaataa tacctgcctt gtaccatttt 3600 ttaaatagaagttacttcat tatattttgc acattatatt taataaaatg 3650 tgtcaatttg aa 3662 2901059 PRT Homo Sapien 290 Met Val Asp Val Leu Leu Leu Phe Ser Leu Cys LeuLeu Phe His 1 5 10 15 Ile Ser Arg Pro Asp Leu Ser His Asn Arg Leu SerPhe Ile Lys 20 25 30 Ala Ser Ser Met Ser His Leu Gln Ser Leu Arg Glu ValLys Leu 35 40 45 Asn Asn Asn Glu Leu Glu Thr Ile Pro Asn Leu Gly Pro ValSer 50 55 60 Ala Asn Ile Thr Leu Leu Ser Leu Ala Gly Asn Arg Ile Val Glu65 70 75 Ile Leu Pro Glu His Leu Lys Glu Phe Gln Ser Leu Glu Thr Leu 8085 90 Asp Leu Ser Ser Asn Asn Ile Ser Glu Leu Gln Thr Ala Phe Pro 95 100105 Ala Leu Gln Leu Lys Tyr Leu Tyr Leu Asn Ser Asn Arg Val Thr 110 115120 Ser Met Glu Pro Gly Tyr Phe Asp Asn Leu Ala Asn Thr Leu Leu 125 130135 Val Leu Lys Leu Asn Arg Asn Arg Ile Ser Ala Ile Pro Pro Lys 140 145150 Met Phe Lys Leu Pro Gln Leu Gln His Leu Glu Leu Asn Arg Asn 155 160165 Lys Ile Lys Asn Val Asp Gly Leu Thr Phe Gln Gly Leu Gly Ala 170 175180 Leu Lys Ser Leu Lys Met Gln Arg Asn Gly Val Thr Lys Leu Met 185 190195 Asp Gly Ala Phe Trp Gly Leu Ser Asn Met Glu Ile Leu Gln Leu 200 205210 Asp His Asn Asn Leu Thr Glu Ile Thr Lys Gly Trp Leu Tyr Gly 215 220225 Leu Leu Met Leu Gln Glu Leu His Leu Ser Gln Asn Ala Ile Asn 230 235240 Arg Ile Ser Pro Asp Ala Trp Glu Phe Cys Gln Lys Leu Ser Glu 245 250255 Leu Asp Leu Thr Phe Asn His Leu Ser Arg Leu Asp Asp Ser Ser 260 265270 Phe Leu Gly Leu Ser Leu Leu Asn Thr Leu His Ile Gly Asn Asn 275 280285 Arg Val Ser Tyr Ile Ala Asp Cys Ala Phe Arg Gly Leu Ser Ser 290 295300 Leu Lys Thr Leu Asp Leu Lys Asn Asn Glu Ile Ser Trp Thr Ile 305 310315 Glu Asp Met Asn Gly Ala Phe Ser Gly Leu Asp Lys Leu Arg Arg 320 325330 Leu Ile Leu Gln Gly Asn Arg Ile Arg Ser Ile Thr Lys Lys Ala 335 340345 Phe Thr Gly Leu Asp Ala Leu Glu His Leu Asp Leu Ser Asp Asn 350 355360 Ala Ile Met Ser Leu Gln Gly Asn Ala Phe Ser Gln Met Lys Lys 365 370375 Leu Gln Gln Leu His Leu Asn Thr Ser Ser Leu Leu Cys Asp Cys 380 385390 Gln Leu Lys Trp Leu Pro Gln Trp Val Ala Glu Asn Asn Phe Gln 395 400405 Ser Phe Val Asn Ala Ser Cys Ala His Pro Gln Leu Leu Lys Gly 410 415420 Arg Ser Ile Phe Ala Val Ser Pro Asp Gly Phe Val Cys Asp Asp 425 430435 Phe Pro Lys Pro Gln Ile Thr Val Gln Pro Glu Thr Gln Ser Ala 440 445450 Ile Lys Gly Ser Asn Leu Ser Phe Ile Cys Ser Ala Ala Ser Ser 455 460465 Ser Asp Ser Pro Met Thr Phe Ala Trp Lys Lys Asp Asn Glu Leu 470 475480 Leu His Asp Ala Glu Met Glu Asn Tyr Ala His Leu Arg Ala Gln 485 490495 Gly Gly Glu Val Met Glu Tyr Thr Thr Ile Leu Arg Leu Arg Glu 500 505510 Val Glu Phe Ala Ser Glu Gly Lys Tyr Gln Cys Val Ile Ser Asn 515 520525 His Phe Gly Ser Ser Tyr Ser Val Lys Ala Lys Leu Thr Val Asn 530 535540 Met Leu Pro Ser Phe Thr Lys Thr Pro Met Asp Leu Thr Ile Arg 545 550555 Ala Gly Ala Met Ala Arg Leu Glu Cys Ala Ala Val Gly His Pro 560 565570 Ala Pro Gln Ile Ala Trp Gln Lys Asp Gly Gly Thr Asp Phe Pro 575 580585 Ala Ala Arg Glu Arg Arg Met His Val Met Pro Glu Asp Asp Val 590 595600 Phe Phe Ile Val Asp Val Lys Ile Glu Asp Ile Gly Val Tyr Ser 605 610615 Cys Thr Ala Gln Asn Ser Ala Gly Ser Ile Ser Ala Asn Ala Thr 620 625630 Leu Thr Val Leu Glu Thr Pro Ser Phe Leu Arg Pro Leu Leu Asp 635 640645 Arg Thr Val Thr Lys Gly Glu Thr Ala Val Leu Gln Cys Ile Ala 650 655660 Gly Gly Ser Pro Pro Pro Lys Leu Asn Trp Thr Lys Asp Asp Ser 665 670675 Pro Leu Val Val Thr Glu Arg His Phe Phe Ala Ala Gly Asn Gln 680 685690 Leu Leu Ile Ile Val Asp Ser Asp Val Ser Asp Ala Gly Lys Tyr 695 700705 Thr Cys Glu Met Ser Asn Thr Leu Gly Thr Glu Arg Gly Asn Val 710 715720 Arg Leu Ser Val Ile Pro Thr Pro Thr Cys Asp Ser Pro Gln Met 725 730735 Thr Ala Pro Ser Leu Asp Asp Asp Gly Trp Ala Thr Val Gly Val 740 745750 Val Ile Ile Ala Val Val Cys Cys Val Val Gly Thr Ser Leu Val 755 760765 Trp Val Val Ile Ile Tyr His Thr Arg Arg Arg Asn Glu Asp Cys 770 775780 Ser Ile Thr Asn Thr Asp Glu Thr Asn Leu Pro Ala Asp Ile Pro 785 790795 Ser Tyr Leu Ser Ser Gln Gly Thr Leu Ala Asp Arg Gln Asp Gly 800 805810 Tyr Val Ser Ser Glu Ser Gly Ser His His Gln Phe Val Thr Ser 815 820825 Ser Gly Ala Gly Phe Phe Leu Pro Gln His Asp Ser Ser Gly Thr 830 835840 Cys His Ile Asp Asn Ser Ser Glu Ala Asp Val Glu Ala Ala Thr 845 850855 Asp Leu Phe Leu Cys Pro Phe Leu Gly Ser Thr Gly Pro Met Tyr 860 865870 Leu Lys Gly Asn Val Tyr Gly Ser Asp Pro Phe Glu Thr Tyr His 875 880885 Thr Gly Cys Ser Pro Asp Pro Arg Thr Val Leu Met Asp His Tyr 890 895900 Glu Pro Ser Tyr Ile Lys Lys Lys Glu Cys Tyr Pro Cys Ser His 905 910915 Pro Ser Glu Glu Ser Cys Glu Arg Ser Phe Ser Asn Ile Ser Trp 920 925930 Pro Ser His Val Arg Lys Leu Leu Asn Thr Ser Tyr Ser His Asn 935 940945 Glu Gly Pro Gly Met Lys Asn Leu Cys Leu Asn Lys Ser Ser Leu 950 955960 Asp Phe Ser Ala Asn Pro Glu Pro Ala Ser Val Ala Ser Ser Asn 965 970975 Ser Phe Met Gly Thr Phe Gly Lys Ala Leu Arg Arg Pro His Leu 980 985990 Asp Ala Tyr Ser Ser Phe Gly Gln Pro Ser Asp Cys Gln Pro Arg 995 10001005 Ala Phe Tyr Leu Lys Ala His Ser Ser Pro Asp Leu Asp Ser Gly 10101015 1020 Ser Glu Glu Asp Gly Lys Glu Arg Thr Asp Phe Gln Glu Glu Asn1025 1030 1035 His Ile Cys Thr Phe Lys Gln Thr Leu Glu Asn Tyr Arg ThrPro 1040 1045 1050 Asn Phe Gln Ser Tyr Asp Leu Asp Thr 1055 291 2906 DNAHomo Sapien 291 ggggagagga attgaccatg taaaaggaga cttttttttt tggtggtggt50 ggctgttggg tgccttgcaa aaatgaagga tgcaggacgc agctttctcc 100 tggaaccgaacgcaatggat aaactgattg tgcaagagag aaggaagaac 150 gaagcttttt cttgtgagccctggatctta acacaaatgt gtatatgtgc 200 acacagggag cattcaagaa tgaaataaaccagagttaga cccgcggggg 250 ttggtgtgtt ctgacataaa taaataatct taaagcagctgttcccctcc 300 ccacccccaa aaaaaaggat gattggaaat gaagaaccga ggattcacaa350 agaaaaaagt atgttcattt ttctctataa aggagaaagt gagccaagga 400gatatttttg gaatgaaaag tttggggctt ttttagtaaa gtaaagaact 450 ggtgtggtggtgttttcctt tctttttgaa tttcccacaa gaggagagga 500 aattaataat acatctgcaaagaaatttca gagaagaaaa gttgaccgcg 550 gcagattgag gcattgattg ggggagagaaaccagcagag cacagttgga 600 tttgtgccta tgttgactaa aattgacgga taattgcagttggatttttc 650 ttcatcaacc tccttttttt taaattttta ttccttttgg tatcaagatc700 atgcgttttc tcttgttctt aaccacctgg atttccatct ggatgttgct 750gtgatcagtc tgaaatacaa ctgtttgaat tccagaagga ccaacaccag 800 ataaattatgaatgttgaac aagatgacct tacatccaca gcagataatg 850 ataggtccta ggtttaacagggccctattt gaccccctgc ttgtggtgct 900 gctggctctt caacttcttg tggtggctggtctggtgcgg gctcagacct 950 gcccttctgt gtgctcctgc agcaaccagt tcagcaaggtgatttgtgtt 1000 cggaaaaacc tgcgtgaggt tccggatggc atctccacca acacacggct1050 gctgaacctc catgagaacc aaatccagat catcaaagtg aacagcttca 1100agcacttgag gcacttggaa atcctacagt tgagtaggaa ccatatcaga 1150 accattgaaattggggcttt caatggtctg gcgaacctca acactctgga 1200 actctttgac aatcgtcttactaccatccc gaatggagct tttgtatact 1250 tgtctaaact gaaggagctc tggttgcgaaacaaccccat tgaaagcatc 1300 ccttcttatg cttttaacag aattccttct ttgcgccgactagacttagg 1350 ggaattgaaa agactttcat acatctcaga aggtgccttt gaaggtctgt1400 ccaacttgag gtatttgaac cttgccatgt gcaaccttcg ggaaatccct 1450aacctcacac cgctcataaa actagatgag ctggatcttt ctgggaatca 1500 tttatctgccatcaggcctg gctctttcca gggtttgatg caccttcaaa 1550 aactgtggat gatacagtcccagattcaag tgattgaacg gaatgccttt 1600 gacaaccttc agtcactagt ggagatcaacctggcacaca ataatctaac 1650 attactgcct catgacctct tcactccctt gcatcatctagagcggatac 1700 atttacatca caacccttgg aactgtaact gtgacatact gtggctcagc1750 tggtggataa aagacatggc cccctcgaac acagcttgtt gtgcccggtg 1800taacactcct cccaatctaa aggggaggta cattggagag ctcgaccaga 1850 attacttcacatgctatgct ccggtgattg tggagccccc tgcagacctc 1900 aatgtcactg aaggcatggcagctgagctg aaatgtcggg cctccacatc 1950 cctgacatct gtatcttgga ttactccaaatggaacagtc atgacacatg 2000 gggcgtacaa agtgcggata gctgtgctca gtgatggtacgttaaatttc 2050 acaaatgtaa ctgtgcaaga tacaggcatg tacacatgta tggtgagtaa2100 ttccgttggg aatactactg cttcagccac cctgaatgtt actgcagcaa 2150ccactactcc tttctcttac ttttcaaccg tcacagtaga gactatggaa 2200 ccgtctcaggatgaggcacg gaccacagat aacaatgtgg gtcccactcc 2250 agtggtcgac tgggagaccaccaatgtgac cacctctctc acaccacaga 2300 gcacaaggtc gacagagaaa accttcaccatcccagtgac tgatataaac 2350 agtgggatcc caggaattga tgaggtcatg aagactaccaaaatcatcat 2400 tgggtgtttt gtggccatca cactcatggc tgcagtgatg ctggtcattt2450 tctacaagat gaggaagcag caccatcggc aaaaccatca cgccccaaca 2500aggactgttg aaattattaa tgtggatgat gagattacgg gagacacacc 2550 catggaaagccacctgccca tgcctgctat cgagcatgag cacctaaatc 2600 actataactc atacaaatctcccttcaacc acacaacaac agttaacaca 2650 ataaattcaa tacacagttc agtgcatgaaccgttattga tccgaatgaa 2700 ctctaaagac aatgtacaag agactcaaat ctaaaacatttacagagtta 2750 caaaaaacaa acaatcaaaa aaaaagacag tttattaaaa atgacacaaa2800 tgactgggct aaatctactg tttcaaaaaa gtgtctttac aaaaaaacaa 2850aaaagaaaag aaatttattt attaaaaatt ctattgtgat ctaaagcaga 2900 caaaaa 2906292 640 PRT Homo Sapien 292 Met Leu Asn Lys Met Thr Leu His Pro Gln GlnIle Met Ile Gly 1 5 10 15 Pro Arg Phe Asn Arg Ala Leu Phe Asp Pro LeuLeu Val Val Leu 20 25 30 Leu Ala Leu Gln Leu Leu Val Val Ala Gly Leu ValArg Ala Gln 35 40 45 Thr Cys Pro Ser Val Cys Ser Cys Ser Asn Gln Phe SerLys Val 50 55 60 Ile Cys Val Arg Lys Asn Leu Arg Glu Val Pro Asp Gly IleSer 65 70 75 Thr Asn Thr Arg Leu Leu Asn Leu His Glu Asn Gln Ile Gln Ile80 85 90 Ile Lys Val Asn Ser Phe Lys His Leu Arg His Leu Glu Ile Leu 95100 105 Gln Leu Ser Arg Asn His Ile Arg Thr Ile Glu Ile Gly Ala Phe 110115 120 Asn Gly Leu Ala Asn Leu Asn Thr Leu Glu Leu Phe Asp Asn Arg 125130 135 Leu Thr Thr Ile Pro Asn Gly Ala Phe Val Tyr Leu Ser Lys Leu 140145 150 Lys Glu Leu Trp Leu Arg Asn Asn Pro Ile Glu Ser Ile Pro Ser 155160 165 Tyr Ala Phe Asn Arg Ile Pro Ser Leu Arg Arg Leu Asp Leu Gly 170175 180 Glu Leu Lys Arg Leu Ser Tyr Ile Ser Glu Gly Ala Phe Glu Gly 185190 195 Leu Ser Asn Leu Arg Tyr Leu Asn Leu Ala Met Cys Asn Leu Arg 200205 210 Glu Ile Pro Asn Leu Thr Pro Leu Ile Lys Leu Asp Glu Leu Asp 215220 225 Leu Ser Gly Asn His Leu Ser Ala Ile Arg Pro Gly Ser Phe Gln 230235 240 Gly Leu Met His Leu Gln Lys Leu Trp Met Ile Gln Ser Gln Ile 245250 255 Gln Val Ile Glu Arg Asn Ala Phe Asp Asn Leu Gln Ser Leu Val 260265 270 Glu Ile Asn Leu Ala His Asn Asn Leu Thr Leu Leu Pro His Asp 275280 285 Leu Phe Thr Pro Leu His His Leu Glu Arg Ile His Leu His His 290295 300 Asn Pro Trp Asn Cys Asn Cys Asp Ile Leu Trp Leu Ser Trp Trp 305310 315 Ile Lys Asp Met Ala Pro Ser Asn Thr Ala Cys Cys Ala Arg Cys 320325 330 Asn Thr Pro Pro Asn Leu Lys Gly Arg Tyr Ile Gly Glu Leu Asp 335340 345 Gln Asn Tyr Phe Thr Cys Tyr Ala Pro Val Ile Val Glu Pro Pro 350355 360 Ala Asp Leu Asn Val Thr Glu Gly Met Ala Ala Glu Leu Lys Cys 365370 375 Arg Ala Ser Thr Ser Leu Thr Ser Val Ser Trp Ile Thr Pro Asn 380385 390 Gly Thr Val Met Thr His Gly Ala Tyr Lys Val Arg Ile Ala Val 395400 405 Leu Ser Asp Gly Thr Leu Asn Phe Thr Asn Val Thr Val Gln Asp 410415 420 Thr Gly Met Tyr Thr Cys Met Val Ser Asn Ser Val Gly Asn Thr 425430 435 Thr Ala Ser Ala Thr Leu Asn Val Thr Ala Ala Thr Thr Thr Pro 440445 450 Phe Ser Tyr Phe Ser Thr Val Thr Val Glu Thr Met Glu Pro Ser 455460 465 Gln Asp Glu Ala Arg Thr Thr Asp Asn Asn Val Gly Pro Thr Pro 470475 480 Val Val Asp Trp Glu Thr Thr Asn Val Thr Thr Ser Leu Thr Pro 485490 495 Gln Ser Thr Arg Ser Thr Glu Lys Thr Phe Thr Ile Pro Val Thr 500505 510 Asp Ile Asn Ser Gly Ile Pro Gly Ile Asp Glu Val Met Lys Thr 515520 525 Thr Lys Ile Ile Ile Gly Cys Phe Val Ala Ile Thr Leu Met Ala 530535 540 Ala Val Met Leu Val Ile Phe Tyr Lys Met Arg Lys Gln His His 545550 555 Arg Gln Asn His His Ala Pro Thr Arg Thr Val Glu Ile Ile Asn 560565 570 Val Asp Asp Glu Ile Thr Gly Asp Thr Pro Met Glu Ser His Leu 575580 585 Pro Met Pro Ala Ile Glu His Glu His Leu Asn His Tyr Asn Ser 590595 600 Tyr Lys Ser Pro Phe Asn His Thr Thr Thr Val Asn Thr Ile Asn 605610 615 Ser Ile His Ser Ser Val His Glu Pro Leu Leu Ile Arg Met Asn 620625 630 Ser Lys Asp Asn Val Gln Glu Thr Gln Ile 635 640 293 4053 DNAHomo Sapien 293 agccgacgct gctcaagctg caactctgtt gcagttggca gttcttttcg50 gtttccctcc tgctgtttgg gggcatgaaa gggcttcgcc gccgggagta 100 aaagaaggaattgaccgggc agcgcgaggg aggagcgcgc acgcgaccgc 150 gagggcgggc gtgcaccctcggctggaagt ttgtgccggg ccccgagcgc 200 gcgccggctg ggagcttcgg gtagagacctaggccgctgg accgcgatga 250 gcgcgccgag cctccgtgcg cgcgccgcgg ggttggggctgctgctgtgc 300 gcggtgctgg ggcgcgctgg ccggtccgac agcggcggtc gcggggaact350 cgggcagccc tctggggtag ccgccgagcg cccatgcccc actacctgcc 400gctgcctcgg ggacctgctg gactgcagtc gtaagcggct agcgcgtctt 450 cccgagccactcccgtcctg ggtcgctcgg ctggacttaa gtcacaacag 500 attatctttc atcaaggcaagttccatgag ccaccttcaa agccttcgag 550 aagtgaaact gaacaacaat gaattggagaccattccaaa tctgggacca 600 gtctcggcaa atattacact tctctccttg gctggaaacaggattgttga 650 aatactccct gaacatctga aagagtttca gtcccttgaa actttggacc700 ttagcagcaa caatatttca gagctccaaa ctgcatttcc agccctacag 750ctcaaatatc tgtatctcaa cagcaaccga gtcacatcaa tggaacctgg 800 gtattttgacaatttggcca acacactcct tgtgttaaag ctgaacagga 850 accgaatctc agctatcccacccaagatgt ttaaactgcc ccaactgcaa 900 catctcgaat tgaaccgaaa caagattaaaaatgtagatg gactgacatt 950 ccaaggcctt ggtgctctga agtctctgaa aatgcaaagaaatggagtaa 1000 cgaaacttat ggatggagct ttttgggggc tgagcaacat ggaaattttg1050 cagctggacc ataacaacct aacagagatt accaaaggct ggctttacgg 1100cttgctgatg ctgcaggaac ttcatctcag ccaaaatgcc atcaacagga 1150 tcagccctgatgcctgggag ttctgccaga agctcagtga gctggaccta 1200 actttcaatc acttatcaaggttagatgat tcaagcttcc ttggcctaag 1250 cttactaaat acactgcaca ttgggaacaacagagtcagc tacattgctg 1300 attgtgcctt ccgggggctt tccagtttaa agactttggatctgaagaac 1350 aatgaaattt cctggactat tgaagacatg aatggtgctt tctctgggct1400 tgacaaactg aggcgactga tactccaagg aaatcggatc cgttctatta 1450ctaaaaaagc cttcactggt ttggatgcat tggagcatct agacctgagt 1500 gacaacgcaatcatgtcttt acaaggcaat gcattttcac aaatgaagaa 1550 actgcaacaa ttgcatttaaatacatcaag ccttttgtgc gattgccagc 1600 taaaatggct cccacagtgg gtggcggaaaacaactttca gagctttgta 1650 aatgccagtt gtgcccatcc tcagctgcta aaaggaagaagcatttttgc 1700 tgttagccca gatggctttg tgtgtgatga ttttcccaaa ccccagatca1750 cggttcagcc agaaacacag tcggcaataa aaggttccaa tttgagtttc 1800atctgctcag ctgccagcag cagtgattcc ccaatgactt ttgcttggaa 1850 aaaagacaatgaactactgc atgatgctga aatggaaaat tatgcacacc 1900 tccgggccca aggtggcgaggtgatggagt ataccaccat ccttcggctg 1950 cgcgaggtgg aatttgccag tgaggggaaatatcagtgtg tcatctccaa 2000 tcactttggt tcatcctact ctgtcaaagc caagcttacagtaaatatgc 2050 ttccctcatt caccaagacc cccatggatc tcaccatccg agctggggcc2100 atggcacgct tggagtgtgc tgctgtgggg cacccagccc cccagatagc 2150ctggcagaag gatgggggca cagacttccc agctgcacgg gagagacgca 2200 tgcatgtgatgcccgaggat gacgtgttct ttatcgtgga tgtgaagata 2250 gaggacattg gggtatacagctgcacagct cagaacagtg caggaagtat 2300 ttcagcaaat gcaactctga ctgtcctagaaacaccatca tttttgcggc 2350 cactgttgga ccgaactgta accaagggag aaacagccgtcctacagtgc 2400 attgctggag gaagccctcc ccctaaactg aactggacca aagatgatag2450 cccattggtg gtaaccgaga ggcacttttt tgcagcaggc aatcagcttc 2500tgattattgt ggactcagat gtcagtgatg ctgggaaata cacatgtgag 2550 atgtctaacacccttggcac tgagagagga aacgtgcgcc tcagtgtgat 2600 ccccactcca acctgcgactcccctcagat gacagcccca tcgttagacg 2650 atgacggatg ggccactgtg ggtgtcgtgatcatagccgt ggtttgctgt 2700 gtggtgggca cgtcactcgt gtgggtggtc atcatataccacacaaggcg 2750 gaggaatgaa gattgcagca ttaccaacac agatgagacc aacttgccag2800 cagatattcc tagttatttg tcatctcagg gaacgttagc tgacaggcag 2850gatgggtacg tgtcttcaga aagtggaagc caccaccagt ttgtcacatc 2900 ttcaggtgctggatttttct taccacaaca tgacagtagt gggacctgcc 2950 atattgacaa tagcagtgaagctgatgtgg aagctgccac agatctgttc 3000 ctttgtccgt ttttgggatc cacaggccctatgtatttga agggaaatgt 3050 gtatggctca gatccttttg aaacatatca tacaggttgcagtcctgacc 3100 caagaacagt tttaatggac cactatgagc ccagttacat aaagaaaaag3150 gagtgctacc catgttctca tccttcagaa gaatcctgcg aacggagctt 3200cagtaatata tcgtggcctt cacatgtgag gaagctactt aacactagtt 3250 actctcacaatgaaggacct ggaatgaaaa atctgtgtct aaacaagtcc 3300 tctttagatt ttagtgcaaatccagagcca gcgtcggttg cctcgagtaa 3350 ttctttcatg ggtacctttg gaaaagctctcaggagacct cacctagatg 3400 cctattcaag ctttggacag ccatcagatt gtcagccaagagccttttat 3450 ttgaaagctc attcttcccc agacttggac tctgggtcag aggaagatgg3500 gaaagaaagg acagattttc aggaagaaaa tcacatttgt acctttaaac 3550agactttaga aaactacagg actccaaatt ttcagtctta tgacttggac 3600 acatagactgaatgagacca aaggaaaagc ttaacatact acctcaagtg 3650 aacttttatt taaaagagagagaatcttat gttttttaaa tggagttatg 3700 aattttaaaa ggataaaaat gctttatttatacagatgaa ccaaaattac 3750 aaaaagttat gaaaattttt atactgggaa tgatgctcatataagaatac 3800 ctttttaaac tattttttaa ctttgtttta tgcaaaaaag tatcttacgt3850 aaattaatga tataaatcat gattatttta tgtattttta taatgccaga 3900tttcttttta tggaaaatga gttactaaag cattttaaat aatacctgcc 3950 ttgtaccattttttaaatag aagttacttc attatatttt gcacattata 4000 tttaataaaa tgtgtcaatttgaaaaaaaa aaaaaaaaaa aaaaaaaaaa 4050 aaa 4053 294 1119 PRT Homo Sapien294 Met Ser Ala Pro Ser Leu Arg Ala Arg Ala Ala Gly Leu Gly Leu 1 5 1015 Leu Leu Cys Ala Val Leu Gly Arg Ala Gly Arg Ser Asp Ser Gly 20 25 30Gly Arg Gly Glu Leu Gly Gln Pro Ser Gly Val Ala Ala Glu Arg 35 40 45 ProCys Pro Thr Thr Cys Arg Cys Leu Gly Asp Leu Leu Asp Cys 50 55 60 Ser ArgLys Arg Leu Ala Arg Leu Pro Glu Pro Leu Pro Ser Trp 65 70 75 Val Ala ArgLeu Asp Leu Ser His Asn Arg Leu Ser Phe Ile Lys 80 85 90 Ala Ser Ser MetSer His Leu Gln Ser Leu Arg Glu Val Lys Leu 95 100 105 Asn Asn Asn GluLeu Glu Thr Ile Pro Asn Leu Gly Pro Val Ser 110 115 120 Ala Asn Ile ThrLeu Leu Ser Leu Ala Gly Asn Arg Ile Val Glu 125 130 135 Ile Leu Pro GluHis Leu Lys Glu Phe Gln Ser Leu Glu Thr Leu 140 145 150 Asp Leu Ser SerAsn Asn Ile Ser Glu Leu Gln Thr Ala Phe Pro 155 160 165 Ala Leu Gln LeuLys Tyr Leu Tyr Leu Asn Ser Asn Arg Val Thr 170 175 180 Ser Met Glu ProGly Tyr Phe Asp Asn Leu Ala Asn Thr Leu Leu 185 190 195 Val Leu Lys LeuAsn Arg Asn Arg Ile Ser Ala Ile Pro Pro Lys 200 205 210 Met Phe Lys LeuPro Gln Leu Gln His Leu Glu Leu Asn Arg Asn 215 220 225 Lys Ile Lys AsnVal Asp Gly Leu Thr Phe Gln Gly Leu Gly Ala 230 235 240 Leu Lys Ser LeuLys Met Gln Arg Asn Gly Val Thr Lys Leu Met 245 250 255 Asp Gly Ala PheTrp Gly Leu Ser Asn Met Glu Ile Leu Gln Leu 260 265 270 Asp His Asn AsnLeu Thr Glu Ile Thr Lys Gly Trp Leu Tyr Gly 275 280 285 Leu Leu Met LeuGln Glu Leu His Leu Ser Gln Asn Ala Ile Asn 290 295 300 Arg Ile Ser ProAsp Ala Trp Glu Phe Cys Gln Lys Leu Ser Glu 305 310 315 Leu Asp Leu ThrPhe Asn His Leu Ser Arg Leu Asp Asp Ser Ser 320 325 330 Phe Leu Gly LeuSer Leu Leu Asn Thr Leu His Ile Gly Asn Asn 335 340 345 Arg Val Ser TyrIle Ala Asp Cys Ala Phe Arg Gly Leu Ser Ser 350 355 360 Leu Lys Thr LeuAsp Leu Lys Asn Asn Glu Ile Ser Trp Thr Ile 365 370 375 Glu Asp Met AsnGly Ala Phe Ser Gly Leu Asp Lys Leu Arg Arg 380 385 390 Leu Ile Leu GlnGly Asn Arg Ile Arg Ser Ile Thr Lys Lys Ala 395 400 405 Phe Thr Gly LeuAsp Ala Leu Glu His Leu Asp Leu Ser Asp Asn 410 415 420 Ala Ile Met SerLeu Gln Gly Asn Ala Phe Ser Gln Met Lys Lys 425 430 435 Leu Gln Gln LeuHis Leu Asn Thr Ser Ser Leu Leu Cys Asp Cys 440 445 450 Gln Leu Lys TrpLeu Pro Gln Trp Val Ala Glu Asn Asn Phe Gln 455 460 465 Ser Phe Val AsnAla Ser Cys Ala His Pro Gln Leu Leu Lys Gly 470 475 480 Arg Ser Ile PheAla Val Ser Pro Asp Gly Phe Val Cys Asp Asp 485 490 495 Phe Pro Lys ProGln Ile Thr Val Gln Pro Glu Thr Gln Ser Ala 500 505 510 Ile Lys Gly SerAsn Leu Ser Phe Ile Cys Ser Ala Ala Ser Ser 515 520 525 Ser Asp Ser ProMet Thr Phe Ala Trp Lys Lys Asp Asn Glu Leu 530 535 540 Leu His Asp AlaGlu Met Glu Asn Tyr Ala His Leu Arg Ala Gln 545 550 555 Gly Gly Glu ValMet Glu Tyr Thr Thr Ile Leu Arg Leu Arg Glu 560 565 570 Val Glu Phe AlaSer Glu Gly Lys Tyr Gln Cys Val Ile Ser Asn 575 580 585 His Phe Gly SerSer Tyr Ser Val Lys Ala Lys Leu Thr Val Asn 590 595 600 Met Leu Pro SerPhe Thr Lys Thr Pro Met Asp Leu Thr Ile Arg 605 610 615 Ala Gly Ala MetAla Arg Leu Glu Cys Ala Ala Val Gly His Pro 620 625 630 Ala Pro Gln IleAla Trp Gln Lys Asp Gly Gly Thr Asp Phe Pro 635 640 645 Ala Ala Arg GluArg Arg Met His Val Met Pro Glu Asp Asp Val 650 655 660 Phe Phe Ile ValAsp Val Lys Ile Glu Asp Ile Gly Val Tyr Ser 665 670 675 Cys Thr Ala GlnAsn Ser Ala Gly Ser Ile Ser Ala Asn Ala Thr 680 685 690 Leu Thr Val LeuGlu Thr Pro Ser Phe Leu Arg Pro Leu Leu Asp 695 700 705 Arg Thr Val ThrLys Gly Glu Thr Ala Val Leu Gln Cys Ile Ala 710 715 720 Gly Gly Ser ProPro Pro Lys Leu Asn Trp Thr Lys Asp Asp Ser 725 730 735 Pro Leu Val ValThr Glu Arg His Phe Phe Ala Ala Gly Asn Gln 740 745 750 Leu Leu Ile IleVal Asp Ser Asp Val Ser Asp Ala Gly Lys Tyr 755 760 765 Thr Cys Glu MetSer Asn Thr Leu Gly Thr Glu Arg Gly Asn Val 770 775 780 Arg Leu Ser ValIle Pro Thr Pro Thr Cys Asp Ser Pro Gln Met 785 790 795 Thr Ala Pro SerLeu Asp Asp Asp Gly Trp Ala Thr Val Gly Val 800 805 810 Val Ile Ile AlaVal Val Cys Cys Val Val Gly Thr Ser Leu Val 815 820 825 Trp Val Val IleIle Tyr His Thr Arg Arg Arg Asn Glu Asp Cys 830 835 840 Ser Ile Thr AsnThr Asp Glu Thr Asn Leu Pro Ala Asp Ile Pro 845 850 855 Ser Tyr Leu SerSer Gln Gly Thr Leu Ala Asp Arg Gln Asp Gly 860 865 870 Tyr Val Ser SerGlu Ser Gly Ser His His Gln Phe Val Thr Ser 875 880 885 Ser Gly Ala GlyPhe Phe Leu Pro Gln His Asp Ser Ser Gly Thr 890 895 900 Cys His Ile AspAsn Ser Ser Glu Ala Asp Val Glu Ala Ala Thr 905 910 915 Asp Leu Phe LeuCys Pro Phe Leu Gly Ser Thr Gly Pro Met Tyr 920 925 930 Leu Lys Gly AsnVal Tyr Gly Ser Asp Pro Phe Glu Thr Tyr His 935 940 945 Thr Gly Cys SerPro Asp Pro Arg Thr Val Leu Met Asp His Tyr 950 955 960 Glu Pro Ser TyrIle Lys Lys Lys Glu Cys Tyr Pro Cys Ser His 965 970 975 Pro Ser Glu GluSer Cys Glu Arg Ser Phe Ser Asn Ile Ser Trp 980 985 990 Pro Ser His ValArg Lys Leu Leu Asn Thr Ser Tyr Ser His Asn 995 1000 1005 Glu Gly ProGly Met Lys Asn Leu Cys Leu Asn Lys Ser Ser Leu 1010 1015 1020 Asp PheSer Ala Asn Pro Glu Pro Ala Ser Val Ala Ser Ser Asn 1025 1030 1035 SerPhe Met Gly Thr Phe Gly Lys Ala Leu Arg Arg Pro His Leu 1040 1045 1050Asp Ala Tyr Ser Ser Phe Gly Gln Pro Ser Asp Cys Gln Pro Arg 1055 10601065 Ala Phe Tyr Leu Lys Ala His Ser Ser Pro Asp Leu Asp Ser Gly 10701075 1080 Ser Glu Glu Asp Gly Lys Glu Arg Thr Asp Phe Gln Glu Glu Asn1085 1090 1095 His Ile Cys Thr Phe Lys Gln Thr Leu Glu Asn Tyr Arg ThrPro 1100 1105 1110 Asn Phe Gln Ser Tyr Asp Leu Asp Thr 1115 295 18 DNAArtificial Sequence Synthetic Oligonucleotide Probe 295 ggaaccgaatctcagcta 18 296 19 DNA Artificial Sequence Synthetic OligonucleotideProbe 296 cctaaactga actggacca 19 297 19 DNA Artificial SequenceSynthetic Oligonucleotide Probe 297 ggctggagac actgaacct 19 298 24 DNAArtificial Sequence Synthetic Oligonucleotide Probe 298 acagctgcacagctcagaac agtg 24 299 22 DNA Artificial Sequence SyntheticOligonucleotide Probe 299 cattcccagt ataaaaattt tc 22 300 18 DNAArtificial Sequence Synthetic Oligonucleotide Probe 300 gggtcttggtgaatgagg 18 301 24 DNA Artificial Sequence Synthetic OligonucleotideProbe 301 gtgcctctcg gttaccacca atgg 24 302 50 DNA Artificial SequenceSynthetic Oligonucleotide Probe 302 gcggccactg ttggaccgaa ctgtaaccaagggagaaaca gccgtcctac 50 303 28 DNA Artificial Sequence SyntheticOligonucleotide Probe 303 gcctttgaca accttcagtc actagtgg 28 304 24 DNAArtificial Sequence Synthetic Oligonucleotide Probe 304 ccccatgtgtccatgactgt tccc 24 305 45 DNA Artificial Sequence SyntheticOligonucleotide Probe 305 tactgcctca tgacctcttc actcccttgc atcatcttagagcgg 45 306 24 DNA Artificial Sequence Synthetic Oligonucleotide Probe306 actccaagga aatcggatcc gttc 24 307 24 DNA Artificial SequenceSynthetic oligonucleotide probe 307 ttagcagctg aggatgggca caac 24 308 24DNA Artificial Sequence Synthetic Oligonucleotide Probe 308 actccaaggaaatcggatcc gttc 24 309 50 DNA Artificial Sequence SyntheticOligonucleotide Probe 309 gccttcactg gtttggatgc attggagcat ctagacctgagtgacaacgc 50 310 3296 DNA Homo Sapien 310 caaaacttgc gtcgcggagagcgcccagct tgacttgaat ggaaggagcc 50 cgagcccgcg gagcgcagct gagactgggggagcgcgttc ggcctgtggg 100 gcgccgctcg gcgccggggc gcagcaggga aggggaagctgtggtctgcc 150 ctgctccacg aggcgccact ggtgtgaacc gggagagccc ctgggtggtc200 ccgtccccta tccctccttt atatagaaac cttccacact gggaaggcag 250cggcgaggca ggagggctca tggtgagcaa ggaggccggc tgatctgcag 300 gcgcacagcattccgagttt acagattttt acagatacca aatggaaggc 350 gaggaggcag aacagcctgcctggttccat cagccctggc gcccaggcgc 400 atctgactcg gcaccccctg caggcaccatggcccagagc cgggtgctgc 450 tgctcctgct gctgctgccg ccacagctgc acctgggacctgtgcttgcc 500 gtgagggccc caggatttgg ccgaagtggc ggccacagcc tgagccccga550 agagaacgaa tttgcggagg aggagccggt gctggtactg agccctgagg 600agcccgggcc tggcccagcc gcggtcagct gcccccgaga ctgtgcctgt 650 tcccaggagggcgtcgtgga ctgtggcggt attgacctgc gtgagttccc 700 gggggacctg cctgagcacaccaaccacct atctctgcag aacaaccagc 750 tggaaaagat ctaccctgag gagctctcccggctgcaccg gctggagaca 800 ctgaacctgc aaaacaaccg cctgacttcc cgagggctcccagagaaggc 850 gtttgagcat ctgaccaacc tcaattacct gtacttggcc aataacaagc900 tgaccttggc accccgcttc ctgccaaacg ccctgatcag tgtggacttt 950gctgccaact atctcaccaa gatctatggg ctcacctttg gccagaagcc 1000 aaacttgaggtctgtgtacc tgcacaacaa caagctggca gacgccgggc 1050 tgccggacaa catgttcaacggctccagca acgtcgaggt cctcatcctg 1100 tccagcaact tcctgcgcca cgtgcccaagcacctgccgc ctgccctgta 1150 caagctgcac ctcaagaaca acaagctgga gaagatccccccgggggcct 1200 tcagcgagct gagcagcctg cgcgagctat acctgcagaa caactacctg1250 actgacgagg gcctggacaa cgagaccttc tggaagctct ccagcctgga 1300gtacctggat ctgtccagca acaacctgtc tcgggtccca gctgggctgc 1350 cgcgcagcctggtgctgctg cacttggaga agaacgccat ccggagcgtg 1400 gacgcgaatg tgctgacccccatccgcagc ctggagtacc tgctgctgca 1450 cagcaaccag ctgcgggagc agggcatccacccactggcc ttccagggcc 1500 tcaagcggtt gcacacggtg cacctgtaca acaacgcgctggagcgcgtg 1550 cccagtggcc tgcctcgccg cgtgcgcacc ctcatgatcc tgcacaacca1600 gatcacaggc attggccgcg aagactttgc caccacctac ttcctggagg 1650agctcaacct cagctacaac cgcatcacca gcccacaggt gcaccgcgac 1700 gccttccgcaagctgcgcct gctgcgctcg ctggacctgt cgggcaaccg 1750 gctgcacacg ctgccacctgggctgcctcg aaatgtccat gtgctgaagg 1800 tcaagcgcaa tgagctggct gccttggcacgaggggcgct ggcgggcatg 1850 gctcagctgc gtgagctgta cctcaccagc aaccgactgcgcagccgagc 1900 cctgggcccc cgtgcctggg tggacctcgc ccatctgcag ctgctggaca1950 tcgccgggaa tcagctcaca gagatccccg aggggctccc cgagtcactt 2000gagtacctgt acctgcagaa caacaagatt agtgcggtgc ccgccaatgc 2050 cttcgactccacgcccaacc tcaaggggat ctttctcagg tttaacaagc 2100 tggctgtggg ctccgtggtggacagtgcct tccggaggct gaagcacctg 2150 caggtcttgg acattgaagg caacttagagtttggtgaca tttccaagga 2200 ccgtggccgc ttggggaagg aaaaggagga ggaggaagaggaggaggagg 2250 aggaagagga aacaagatag tgacaaggtg atgcagatgt gacctaggat2300 gatggaccgc cggactcttt tctgcagcac acgcctgtgt gctgtgagcc 2350ccccactctg ccgtgctcac acagacacac ccagctgcac acatgaggca 2400 tcccacatgacacgggctga cacagtctca tatccccacc ccttcccacg 2450 gcgtgtccca cggccagacacatgcacaca catcacaccc tcaaacaccc 2500 agctcagcca cacacaacta ccctccaaaccaccacagtc tctgtcacac 2550 ccccactacc gctgccacgc cctctgaatc atgcagggaagggtctgccc 2600 ctgccctggc acacacaggc acccattccc tccccctgct gacatgtgta2650 tgcgtatgca tacacaccac acacacacac atgcacaagt catgtgcgaa 2700cagccctcca aagcctatgc cacagacagc tcttgcccca gccagaatca 2750 gccatagcagctcgccgtct gccctgtcca tctgtccgtc cgttccctgg 2800 agaagacaca agggtatccatgctctgtgg ccaggtgcct gccaccctct 2850 ggaactcaca aaagctggct tttattcctttcccatccta tggggacagg 2900 agccttcagg actgctggcc tggcctggcc caccctgctcctccaggtgc 2950 tgggcagtca ctctgctaag agtccctccc tgccacgccc tggcaggaca3000 caggcacttt tccaatgggc aagcccagtg gaggcaggat gggagagccc 3050cctgggtgct gctggggcct tggggcagga gtgaagcaga ggtgatgggg 3100 ctgggctgagccagggagga aggacccagc tgcacctagg agacaccttt 3150 gttcttcagg cctgtgggggaagttccggg tgcctttatt ttttattctt 3200 ttctaaggaa aaaaatgata aaaatctcaaagctgatttt tcttgttata 3250 gaaaaactaa tataaaagca ttatccctat ccctgcaaaaaaaaaa 3296 311 22 DNA Artificial Sequence Synthetic OligonucleotideProbe 311 gcattggccg cgagactttg cc 22 312 22 DNA Artificial SequenceSynthetic Oligonucleotide Probe 312 gcggccacgg tccttggaaa tg 22 313 45DNA Artificial Sequence Synthetic Oligonucleotide Probe 313 tggaggagctcaacctcagc tacaaccgca tcaccagccc acagg 45 314 3003 DNA Homo Sapien 314gggagggggc tccgggcgcc gcgcagcaga cctgctccgg ccgcgcgcct 50 cgccgctgtcctccgggagc ggcagcagta gcccgggcgg cgagggctgg 100 gggttcctcg agactctcagaggggcgcct cccatcggcg cccaccaccc 150 caacctgttc ctcgcgcgcc actgcgctgcgccccaggac ccgctgccca 200 acatggattt tctcctggcg ctggtgctgg tatcctcgctctacctgcag 250 gcggccgccg agttcgacgg gaggtggccc aggcaaatag tgtcatcgat300 tggcctatgt cgttatggtg ggaggattga ctgctgctgg ggctgggctc 350gccagtcttg gggacagtgt cagcctgtgt gccaaccacg atgcaaacat 400 ggtgaatgtatcgggccaaa caagtgcaag tgtcatcctg gttatgctgg 450 aaaaacctgt aatcaagatctaaatgagtg tggcctgaag ccccggccct 500 gtaagcacag gtgcatgaac acttacggcagctacaagtg ctactgtctc 550 aacggatata tgctcatgcc ggatggttcc tgctcaagtgccctgacctg 600 ctccatggca aactgtcagt atggctgtga tgttgttaaa ggacaaatac650 ggtgccagtg cccatcccct ggcctgcacc tggctcctga tgggaggacc 700tgtgtagatg ttgatgaatg tgctacagga agagcctcct gccctagatt 750 taggcaatgtgtcaacactt ttgggagcta catctgcaag tgtcataaag 800 gcttcgatct catgtatattggaggcaaat atcaatgtca tgacatagac 850 gaatgctcac ttggtcagta tcagtgcagcagctttgctc gatgttataa 900 cgtacgtggg tcctacaagt gcaaatgtaa agaaggataccagggtgatg 950 gactgacttg tgtgtatatc ccaaaagtta tgattgaacc ttcaggtcca1000 attcatgtac caaagggaaa tggtaccatt ttaaagggtg acacaggaaa 1050taataattgg attcctgatg ttggaagtac ttggtggcct ccgaagacac 1100 catatattcctcctatcatt accaacaggc ctacttctaa gccaacaaca 1150 agacctacac caaagccaacaccaattcct actccaccac caccaccacc 1200 cctgccaaca gagctcagaa cacctctaccacctacaacc ccagaaaggc 1250 caaccaccgg actgacaact atagcaccag ctgccagtacacctccagga 1300 gggattacag ttgacaacag ggtacagaca gaccctcaga aacccagagg1350 agatgtgttc agtgttctgg tacacagttg taattttgac catggacttt 1400gtggatggat cagggagaaa gacaatgact tgcactggga accaatcagg 1450 gacccagcaggtggacaata tctgacagtg tcggcagcca aagccccagg 1500 gggaaaagct gcacgcttggtgctacctct cggccgcctc atgcattcag 1550 gggacctgtg cctgtcattc aggcacaaggtgacggggct gcactctggc 1600 acactccagg tgtttgtgag aaaacacggt gcccacggagcagccctgtg 1650 gggaagaaat ggtggccatg gctggaggca aacacagatc accttgcgag1700 gggctgacat caagagcgaa tcacaaagat gattaaaggg ttggaaaaaa 1750agatctatga tggaaaatta aaggaactgg gattattgag cctggagaag 1800 agaagactgaggggcaaacc attgatggtt ttcaagtata tgaagggttg 1850 gcacagagag ggtggcgaccagctgttctc catatgcact aagaatagaa 1900 caagaggaaa ctggcttaga ctagagtataagggagcatt tcttggcagg 1950 ggccattgtt agaatacttc ataaaaaaag aagtgtgaaaatctcagtat 2000 ctctctctct ttctaaaaaa ttagataaaa atttgtctat ttaagatggt2050 taaagatgtt cttacccaag gaaaagtaac aaattataga atttcccaaa 2100agatgttttg atcctactag tagtatgcag tgaaaatctt tagaactaaa 2150 taatttggacaaggcttaat ttaggcattt ccctcttgac ctcctaatgg 2200 agagggattg aaaggggaagagcccaccaa atgctgagct cactgaaata 2250 tctctccctt atggcaatcc tagcagtattaaagaaaaaa ggaaactatt 2300 tattccaaat gagagtatga tggacagata ttttagtatctcagtaatgt 2350 cctagtgtgg cggtggtttt caatgtttct tcatggtaaa ggtataagcc2400 tttcatttgt tcaatggatg atgtttcaga tttttttttt tttaagagat 2450ccttcaagga acacagttca gagagatttt catcgggtgc attctctctg 2500 cttcgtgtgtgacaagttat cttggctgct gagaaagagt gccctgcccc 2550 acaccggcag acctttccttcacctcatca gtatgattca gtttctctta 2600 tcaattggac tctcccaggt tccacagaacagtaatattt tttgaacaat 2650 aggtacaata gaaggtcttc tgtcatttaa cctggtaaaggcagggctgg 2700 agggggaaaa taaatcatta agcctttgag taacggcaga atatatggct2750 gtagatccat ttttaatggt tcatttcctt tatggtcata taactgcaca 2800gctgaagatg aaaggggaaa ataaatgaaa attttacttt tcgatgccaa 2850 tgatacattgcactaaactg atggaagaag ttatccaaag tactgtataa 2900 catcttgttt attatttaatgttttctaaa ataaaaaatg ttagtggttt 2950 tccaaatggc ctaataaaaa caattatttgtaaataaaaa cactgttagt 3000 aat 3003 315 509 PRT Homo Sapien 315 Met AspPhe Leu Leu Ala Leu Val Leu Val Ser Ser Leu Tyr Leu 1 5 10 15 Gln AlaAla Ala Glu Phe Asp Gly Arg Trp Pro Arg Gln Ile Val 20 25 30 Ser Ser IleGly Leu Cys Arg Tyr Gly Gly Arg Ile Asp Cys Cys 35 40 45 Trp Gly Trp AlaArg Gln Ser Trp Gly Gln Cys Gln Pro Val Cys 50 55 60 Gln Pro Arg Cys LysHis Gly Glu Cys Ile Gly Pro Asn Lys Cys 65 70 75 Lys Cys His Pro Gly TyrAla Gly Lys Thr Cys Asn Gln Asp Leu 80 85 90 Asn Glu Cys Gly Leu Lys ProArg Pro Cys Lys His Arg Cys Met 95 100 105 Asn Thr Tyr Gly Ser Tyr LysCys Tyr Cys Leu Asn Gly Tyr Met 110 115 120 Leu Met Pro Asp Gly Ser CysSer Ser Ala Leu Thr Cys Ser Met 125 130 135 Ala Asn Cys Gln Tyr Gly CysAsp Val Val Lys Gly Gln Ile Arg 140 145 150 Cys Gln Cys Pro Ser Pro GlyLeu His Leu Ala Pro Asp Gly Arg 155 160 165 Thr Cys Val Asp Val Asp GluCys Ala Thr Gly Arg Ala Ser Cys 170 175 180 Pro Arg Phe Arg Gln Cys ValAsn Thr Phe Gly Ser Tyr Ile Cys 185 190 195 Lys Cys His Lys Gly Phe AspLeu Met Tyr Ile Gly Gly Lys Tyr 200 205 210 Gln Cys His Asp Ile Asp GluCys Ser Leu Gly Gln Tyr Gln Cys 215 220 225 Ser Ser Phe Ala Arg Cys TyrAsn Val Arg Gly Ser Tyr Lys Cys 230 235 240 Lys Cys Lys Glu Gly Tyr GlnGly Asp Gly Leu Thr Cys Val Tyr 245 250 255 Ile Pro Lys Val Met Ile GluPro Ser Gly Pro Ile His Val Pro 260 265 270 Lys Gly Asn Gly Thr Ile LeuLys Gly Asp Thr Gly Asn Asn Asn 275 280 285 Trp Ile Pro Asp Val Gly SerThr Trp Trp Pro Pro Lys Thr Pro 290 295 300 Tyr Ile Pro Pro Ile Ile ThrAsn Arg Pro Thr Ser Lys Pro Thr 305 310 315 Thr Arg Pro Thr Pro Lys ProThr Pro Ile Pro Thr Pro Pro Pro 320 325 330 Pro Pro Pro Leu Pro Thr GluLeu Arg Thr Pro Leu Pro Pro Thr 335 340 345 Thr Pro Glu Arg Pro Thr ThrGly Leu Thr Thr Ile Ala Pro Ala 350 355 360 Ala Ser Thr Pro Pro Gly GlyIle Thr Val Asp Asn Arg Val Gln 365 370 375 Thr Asp Pro Gln Lys Pro ArgGly Asp Val Phe Ser Val Leu Val 380 385 390 His Ser Cys Asn Phe Asp HisGly Leu Cys Gly Trp Ile Arg Glu 395 400 405 Lys Asp Asn Asp Leu His TrpGlu Pro Ile Arg Asp Pro Ala Gly 410 415 420 Gly Gln Tyr Leu Thr Val SerAla Ala Lys Ala Pro Gly Gly Lys 425 430 435 Ala Ala Arg Leu Val Leu ProLeu Gly Arg Leu Met His Ser Gly 440 445 450 Asp Leu Cys Leu Ser Phe ArgHis Lys Val Thr Gly Leu His Ser 455 460 465 Gly Thr Leu Gln Val Phe ValArg Lys His Gly Ala His Gly Ala 470 475 480 Ala Leu Trp Gly Arg Asn GlyGly His Gly Trp Arg Gln Thr Gln 485 490 495 Ile Thr Leu Arg Gly Ala AspIle Lys Ser Glu Ser Gln Arg 500 505 316 24 DNA Artificial SequenceSynthetic Oligonucleotide Probe 316 gatggttcct gctcaagtgc cctg 24 317 24DNA Artificial Sequence Synthetic Oligonucleotide Probe 317 ttgcacttgtaggacccacg tacg 24 318 50 DNA Artificial Sequence SyntheticOligonucleotide Probe 318 ctgatgggag gacctgtgta gatgttgatg aatgtgctacaggaagagcc 50 319 2110 DNA Homo Sapien 319 cttctttgaa aaggattatcacctgatcag gttctctctg catttgcccc 50 tttagattgt gaaatgtggc tcaaggtcttcacaactttc ctttcctttg 100 caacaggtgc ttgctcgggg ctgaaggtga cagtgccatcacacactgtc 150 catggcgtca gaggtcaggc cctctaccta cccgtccact atggcttcca200 cactccagca tcagacatcc agatcatatg gctatttgag agaccccaca 250caatgcccaa atacttactg ggctctgtga ataagtctgt ggttcctgac 300 ttggaataccaacacaagtt caccatgatg ccacccaatg catctctgct 350 tatcaaccca ctgcagttccctgatgaagg caattacatc gtgaaggtca 400 acattcaggg aaatggaact ctatctgccagtcagaagat acaagtcacg 450 gttgatgatc ctgtcacaaa gccagtggtg cagattcatcctccctctgg 500 ggctgtggag tatgtgggga acatgaccct gacatgccat gtggaagggg550 gcactcggct agcttaccaa tggctaaaaa atgggagacc tgtccacacc 600agctccacct actccttttc tccccaaaac aatacccttc atattgctcc 650 agtaaccaaggaagacattg ggaattacag ctgcctggtg aggaaccctg 700 tcagtgaaat ggaaagtgatatcattatgc ccatcatata ttatggacct 750 tatggacttc aagtgaattc tgataaagggctaaaagtag gggaagtgtt 800 tactgttgac cttggagagg ccatcctatt tgattgttctgctgattctc 850 atccccccaa cacctactcc tggattagga ggactgacaa tactacatat900 atcattaagc atgggcctcg cttagaagtt gcatctgaga aagtagccca 950gaagacaatg gactatgtgt gctgtgctta caacaacata accggcaggc 1000 aagatgaaactcatttcaca gttatcatca cttccgtagg actggagaag 1050 cttgcacaga aaggaaaatcattgtcacct ttagcaagta taactggaat 1100 atcactattt ttgattatat ccatgtgtcttctcttccta tggaaaaaat 1150 atcaacccta caaagttata aaacagaaac tagaaggcaggccagaaaca 1200 gaatacagga aagctcaaac attttcaggc catgaagatg ctctggatga1250 cttcggaata tatgaatttg ttgcttttcc agatgtttct ggtgtttcca 1300ggattccaag caggtctgtt ccagcctctg attgtgtatc ggggcaagat 1350 ttgcacagtacagtgtatga agttattcag cacatccctg cccagcagca 1400 agaccatcca gagtgaactttcatgggcta aacagtacat tcgagtgaaa 1450 ttctgaagaa acattttaag gaaaaacagtggaaaagtat attaatctgg 1500 aatcagtgaa gaaaccagga ccaacacctc ttactcattattcctttaca 1550 tgcagaatag aggcatttat gcaaattgaa ctgcaggttt ttcagcatat1600 acacaatgtc ttgtgcaaca gaaaaacatg ttggggaaat attcctcagt 1650ggagagtcgt tctcatgctg acggggagaa cgaaagtgac aggggtttcc 1700 tcataagttttgtatgaaat atctctacaa acctcaatta gttctactct 1750 acactttcac tatcatcaacactgagacta tcctgtctca cctacaaatg 1800 tggaaacttt acattgttcg atttttcagcagactttgtt ttattaaatt 1850 tttattagtg ttaagaatgc taaatttatg tttcaattttatttccaaat 1900 ttctatcttg ttatttgtac aacaaagtaa taaggatggt tgtcacaaaa1950 acaaaactat gccttctctt ttttttcaat caccagtagt atttttgaga 2000agacttgtga acacttaagg aaatgactat taaagtctta tttttatttt 2050 tttcaaggaaagatggattc aaataaatta ttctgttttt gcttttaaaa 2100 aaaaaaaaaa 2110 320 450PRT Homo Sapien 320 Met Trp Leu Lys Val Phe Thr Thr Phe Leu Ser Phe AlaThr Gly 1 5 10 15 Ala Cys Ser Gly Leu Lys Val Thr Val Pro Ser His ThrVal His 20 25 30 Gly Val Arg Gly Gln Ala Leu Tyr Leu Pro Val His Tyr GlyPhe 35 40 45 His Thr Pro Ala Ser Asp Ile Gln Ile Ile Trp Leu Phe Glu Arg50 55 60 Pro His Thr Met Pro Lys Tyr Leu Leu Gly Ser Val Asn Lys Ser 6570 75 Val Val Pro Asp Leu Glu Tyr Gln His Lys Phe Thr Met Met Pro 80 8590 Pro Asn Ala Ser Leu Leu Ile Asn Pro Leu Gln Phe Pro Asp Glu 95 100105 Gly Asn Tyr Ile Val Lys Val Asn Ile Gln Gly Asn Gly Thr Leu 110 115120 Ser Ala Ser Gln Lys Ile Gln Val Thr Val Asp Asp Pro Val Thr 125 130135 Lys Pro Val Val Gln Ile His Pro Pro Ser Gly Ala Val Glu Tyr 140 145150 Val Gly Asn Met Thr Leu Thr Cys His Val Glu Gly Gly Thr Arg 155 160165 Leu Ala Tyr Gln Trp Leu Lys Asn Gly Arg Pro Val His Thr Ser 170 175180 Ser Thr Tyr Ser Phe Ser Pro Gln Asn Asn Thr Leu His Ile Ala 185 190195 Pro Val Thr Lys Glu Asp Ile Gly Asn Tyr Ser Cys Leu Val Arg 200 205210 Asn Pro Val Ser Glu Met Glu Ser Asp Ile Ile Met Pro Ile Ile 215 220225 Tyr Tyr Gly Pro Tyr Gly Leu Gln Val Asn Ser Asp Lys Gly Leu 230 235240 Lys Val Gly Glu Val Phe Thr Val Asp Leu Gly Glu Ala Ile Leu 245 250255 Phe Asp Cys Ser Ala Asp Ser His Pro Pro Asn Thr Tyr Ser Trp 260 265270 Ile Arg Arg Thr Asp Asn Thr Thr Tyr Ile Ile Lys His Gly Pro 275 280285 Arg Leu Glu Val Ala Ser Glu Lys Val Ala Gln Lys Thr Met Asp 290 295300 Tyr Val Cys Cys Ala Tyr Asn Asn Ile Thr Gly Arg Gln Asp Glu 305 310315 Thr His Phe Thr Val Ile Ile Thr Ser Val Gly Leu Glu Lys Leu 320 325330 Ala Gln Lys Gly Lys Ser Leu Ser Pro Leu Ala Ser Ile Thr Gly 335 340345 Ile Ser Leu Phe Leu Ile Ile Ser Met Cys Leu Leu Phe Leu Trp 350 355360 Lys Lys Tyr Gln Pro Tyr Lys Val Ile Lys Gln Lys Leu Glu Gly 365 370375 Arg Pro Glu Thr Glu Tyr Arg Lys Ala Gln Thr Phe Ser Gly His 380 385390 Glu Asp Ala Leu Asp Asp Phe Gly Ile Tyr Glu Phe Val Ala Phe 395 400405 Pro Asp Val Ser Gly Val Ser Arg Ile Pro Ser Arg Ser Val Pro 410 415420 Ala Ser Asp Cys Val Ser Gly Gln Asp Leu His Ser Thr Val Tyr 425 430435 Glu Val Ile Gln His Ile Pro Ala Gln Gln Gln Asp His Pro Glu 440 445450 321 25 DNA Artificial Sequence Synthetic Oligonucleotide Probe 321gatcctgtca caaagccagt ggtgc 25 322 24 DNA Artificial Sequence SyntheticOligonucleotide Probe 322 cactgacagg gttcctcacc cagg 24 323 45 DNAArtificial Sequence Synthetic Oligonucleotide Probe 323 ctccctctgggctgtggagt atgtggggaa catgaccctg acatg 45 324 2397 DNA Homo Sapien 324gcaagcggcg aaatggcgcc ctccgggagt cttgcagttc ccctggcagt 50 cctggtgctgttgctttggg gtgctccctg gacgcacggg cggcggagca 100 acgttcgcgt catcacggacgagaactgga gagaactgct ggaaggagac 150 tggatgatag aattttatgc cccgtggtgccctgcttgtc aaaatcttca 200 accggaatgg gaaagttttg ctgaatgggg agaagatcttgaggttaata 250 ttgcgaaagt agatgtcaca gagcagccag gactgagtgg acggtttatc300 ataactgctc ttcctactat ttatcattgt aaagatggtg aatttaggcg 350ctatcagggt ccaaggacta agaaggactt cataaacttt ataagtgata 400 aagagtggaagagtattgag cccgtttcat catggtttgg tccaggttct 450 gttctgatga gtagtatgtcagcactcttt cagctatcta tgtggatcag 500 gacgtgccat aactacttta ttgaagaccttggattgcca gtgtggggat 550 catatactgt ttttgcttta gcaactctgt tttccggactgttattagga 600 ctctgtatga tatttgtggc agattgcctt tgtccttcaa aaaggcgcag650 accacagcca tacccatacc cttcaaaaaa attattatca gaatctgcac 700aacctttgaa aaaagtggag gaggaacaag aggcggatga agaagatgtt 750 tcagaagaagaagctgaaag taaagaagga acaaacaaag actttccaca 800 gaatgccata agacaacgctctctgggtcc atcattggcc acagataaat 850 cctagttaaa ttttatagtt atcttaatattatgattttg ataaaaacag 900 aagattgatc attttgtttg gtttgaagtg aactgtgacttttttgaata 950 ttgcagggtt cagtctagat tgtcattaaa ttgaagagtc tacattcaga1000 acataaaagc actaggtata caagtttgaa atatgattta agcacagtat 1050gatggtttaa atagttctct aatttttgaa aaatcgtgcc aagcaataag 1100 atttatgtatatttgtttaa taataaccta tttcaagtct gagttttgaa 1150 aatttacatt tcccaagtattgcattattg aggtatttaa gaagattatt 1200 ttagagaaaa atatttctca tttgatataatttttctctg tttcactgtg 1250 tgaaaaaaag aagatatttc ccataaatgg gaagtttgcccattgtctca 1300 agaaatgtgt atttcagtga caatttcgtg gtctttttag aggtatattc1350 caaaatttcc ttgtattttt aggttatgca actaataaaa actaccttac 1400attaattaat tacagttttc tacacatggt aatacaggat atgctactga 1450 tttaggaagtttttaagttc atggtattct cttgattcca acaaagtttg 1500 attttctctt gtatttttcttacttactat gggttacatt ttttattttt 1550 caaattggat gataatttct tggaaacattttttatgttt tagtaaacag 1600 tatttttttg ttgtttcaaa ctgaagttta ctgagagatccatcaaattg 1650 aacaatctgt tgtaatttaa aattttggcc acttttttca gattttacat1700 cattcttgct gaacttcaac ttgaaattgt tttttttttc tttttggatg 1750tgaaggtgaa cattcctgat ttttgtctga tgtgaaaaag ccttggtatt 1800 ttacattttgaaaattcaaa gaagcttaat ataaaagttt gcattctact 1850 caggaaaaag catcttcttgtatatgtctt aaatgtattt ttgtcctcat 1900 atacagaaag ttcttaattg attttacagtctgtaatgct tgatgtttta 1950 aaataataac atttttatat tttttaaaag acaaacttcatattatcctg 2000 tgttctttcc tgactggtaa tattgtgtgg gatttcacag gtaaaagtca2050 gtaggatgga acattttagt gtatttttac tccttaaaga gctagaatac 2100atagttttca ccttaaaaga agggggaaaa tcataaatac aatgaatcaa 2150 ctgaccattacgtagtagac aatttctgta atgtcccctt ctttctaggc 2200 tctgttgctg tgtgaatccattagatttac agtatcgtaa tatacaagtt 2250 ttctttaaag ccctctcctt tagaatttaaaatattgtac cattaaagag 2300 tttggatgtg taacttgtga tgccttagaa aaatatcctaagcacaaaat 2350 aaacctttct aaccacttca ttaaagctga aaaaaaaaaa aaaaaaa 2397325 280 PRT Homo Sapien 325 Met Ala Pro Ser Gly Ser Leu Ala Val Pro LeuAla Val Leu Val 1 5 10 15 Leu Leu Leu Trp Gly Ala Pro Trp Thr His GlyArg Arg Ser Asn 20 25 30 Val Arg Val Ile Thr Asp Glu Asn Trp Arg Glu LeuLeu Glu Gly 35 40 45 Asp Trp Met Ile Glu Phe Tyr Ala Pro Trp Cys Pro AlaCys Gln 50 55 60 Asn Leu Gln Pro Glu Trp Glu Ser Phe Ala Glu Trp Gly GluAsp 65 70 75 Leu Glu Val Asn Ile Ala Lys Val Asp Val Thr Glu Gln Pro Gly80 85 90 Leu Ser Gly Arg Phe Ile Ile Thr Ala Leu Pro Thr Ile Tyr His 95100 105 Cys Lys Asp Gly Glu Phe Arg Arg Tyr Gln Gly Pro Arg Thr Lys 110115 120 Lys Asp Phe Ile Asn Phe Ile Ser Asp Lys Glu Trp Lys Ser Ile 125130 135 Glu Pro Val Ser Ser Trp Phe Gly Pro Gly Ser Val Leu Met Ser 140145 150 Ser Met Ser Ala Leu Phe Gln Leu Ser Met Trp Ile Arg Thr Cys 155160 165 His Asn Tyr Phe Ile Glu Asp Leu Gly Leu Pro Val Trp Gly Ser 170175 180 Tyr Thr Val Phe Ala Leu Ala Thr Leu Phe Ser Gly Leu Leu Leu 185190 195 Gly Leu Cys Met Ile Phe Val Ala Asp Cys Leu Cys Pro Ser Lys 200205 210 Arg Arg Arg Pro Gln Pro Tyr Pro Tyr Pro Ser Lys Lys Leu Leu 215220 225 Ser Glu Ser Ala Gln Pro Leu Lys Lys Val Glu Glu Glu Gln Glu 230235 240 Ala Asp Glu Glu Asp Val Ser Glu Glu Glu Ala Glu Ser Lys Glu 245250 255 Gly Thr Asn Lys Asp Phe Pro Gln Asn Ala Ile Arg Gln Arg Ser 260265 270 Leu Gly Pro Ser Leu Ala Thr Asp Lys Ser 275 280 326 23 DNAArtificial Sequence Synthetic Oligonucleotide Probe 326 tgaggtgggcaagcggcgaa atg 23 327 20 DNA Artificial Sequence SyntheticOligonucleotide Probe 327 tatgtggatc aggacgtgcc 20 328 21 DNA ArtificialSequence Synthetic Oligonucleotide Probe 328 tgcagggttc agtctagatt g 21329 25 DNA Artificial Sequence Synthetic Oligonucleotide Probe 329ttgaaggaca aaggcaatct gccac 25 330 45 DNA Artificial Sequence SyntheticOligonucleotide Probe 330 ggagtcttgc agttcccctg gcagtcctgg tgctgttgctttggg 45 331 2168 DNA Homo Sapien 331 gcgagtgtcc agctgcggag acccgtgataattcgttaac taattcaaca 50 aacgggaccc ttctgtgtgc cagaaaccgc aagcagttgctaacccagtg 100 ggacaggcgg attggaagag cgggaaggtc ctggcccaga gcagtgtgac150 acttccctct gtgaccatga aactctgggt gtctgcattg ctgatggcct 200ggtttggtgt cctgagctgt gtgcaggccg aattcttcac ctctattggg 250 cacatgactgacctgattta tgcagagaaa gagctggtgc agtctctgaa 300 agagtacatc cttgtggaggaagccaagct ttccaagatt aagagctggg 350 ccaacaaaat ggaagccttg actagcaagtcagctgctga tgctgagggc 400 tacctggctc accctgtgaa tgcctacaaa ctggtgaagcggctaaacac 450 agactggcct gcgctggagg accttgtcct gcaggactca gctgcaggtt500 ttatcgccaa cctctctgtg cagcggcagt tcttccccac tgatgaggac 550gagataggag ctgccaaagc cctgatgaga cttcaggaca catacaggct 600 ggacccaggcacaatttcca gaggggaact tccaggaacc aagtaccagg 650 caatgctgag tgtggatgactgctttggga tgggccgctc ggcctacaat 700 gaaggggact attatcatac ggtgttgtggatggagcagg tgctaaagca 750 gcttgatgcc ggggaggagg ccaccacaac caagtcacaggtgctggact 800 acctcagcta tgctgtcttc cagttgggtg atctgcaccg tgccctggag850 ctcacccgcc gcctgctctc ccttgaccca agccacgaac gagctggagg 900gaatctgcgg tactttgagc agttattgga ggaagagaga gaaaaaacgt 950 taacaaatcagacagaagct gagctagcaa ccccagaagg catctatgag 1000 aggcctgtgg actacctgcctgagagggat gtttacgaga gcctctgtcg 1050 tggggagggt gtcaaactga caccccgtagacagaagagg cttttctgta 1100 ggtaccacca tggcaacagg gccccacagc tgctcattgcccccttcaaa 1150 gaggaggacg agtgggacag cccgcacatc gtcaggtact acgatgtcat1200 gtctgatgag gaaatcgaga ggatcaagga gatcgcaaaa cctaaacttg 1250cacgagccac cgttcgtgat cccaagacag gagtcctcac tgtcgccagc 1300 taccgggtttccaaaagctc ctggctagag gaagatgatg accctgttgt 1350 ggcccgagta aatcgtcggatgcagcatat cacagggtta acagtaaaga 1400 ctgcagaatt gttacaggtt gcaaattatggagtgggagg acagtatgaa 1450 ccgcacttcg acttctctag gcgacctttt gacagcggcctcaaaacaga 1500 ggggaatagg ttagcgacgt ttcttaacta catgagtgat gtagaagctg1550 gtggtgccac cgtcttccct gatctggggg ctgcaatttg gcctaagaag 1600ggtacagctg tgttctggta caacctcttg cggagcgggg aaggtgacta 1650 ccgaacaagacatgctgcct gccctgtgct tgtgggctgc aagtgggtct 1700 ccaataagtg gttccatgaacgaggacagg agttcttgag accttgtgga 1750 tcaacagaag ttgactgaca tccttttctgtccttcccct tcctggtcct 1800 tcagcccatg tcaacgtgac agacaccttt gtatgttcctttgtatgttc 1850 ctatcaggct gatttttgga gaaatgaatg tttgtctgga gcagagggag1900 accatactag ggcgactcct gtgtgactga agtcccagcc cttccattca 1950gcctgtgcca tccctggccc caaggctagg atcaaagtgg ctgcagcaga 2000 gttagctgtctagcgcctag caaggtgcct ttgtacctca ggtgttttag 2050 gtgtgagatg tttcagtgaaccaaagttct gataccttgt ttacatgttt 2100 gtttttatgg catttctatc tattgtggctttaccaaaaa ataaaatgtc 2150 cctaccagaa aaaaaaaa 2168 332 533 PRT HomoSapien 332 Met Lys Leu Trp Val Ser Ala Leu Leu Met Ala Trp Phe Gly Val 15 10 15 Leu Ser Cys Val Gln Ala Glu Phe Phe Thr Ser Ile Gly His Met 2025 30 Thr Asp Leu Ile Tyr Ala Glu Lys Glu Leu Val Gln Ser Leu Lys 35 4045 Glu Tyr Ile Leu Val Glu Glu Ala Lys Leu Ser Lys Ile Lys Ser 50 55 60Trp Ala Asn Lys Met Glu Ala Leu Thr Ser Lys Ser Ala Ala Asp 65 70 75 AlaGlu Gly Tyr Leu Ala His Pro Val Asn Ala Tyr Lys Leu Val 80 85 90 Lys ArgLeu Asn Thr Asp Trp Pro Ala Leu Glu Asp Leu Val Leu 95 100 105 Gln AspSer Ala Ala Gly Phe Ile Ala Asn Leu Ser Val Gln Arg 110 115 120 Gln PhePhe Pro Thr Asp Glu Asp Glu Ile Gly Ala Ala Lys Ala 125 130 135 Leu MetArg Leu Gln Asp Thr Tyr Arg Leu Asp Pro Gly Thr Ile 140 145 150 Ser ArgGly Glu Leu Pro Gly Thr Lys Tyr Gln Ala Met Leu Ser 155 160 165 Val AspAsp Cys Phe Gly Met Gly Arg Ser Ala Tyr Asn Glu Gly 170 175 180 Asp TyrTyr His Thr Val Leu Trp Met Glu Gln Val Leu Lys Gln 185 190 195 Leu AspAla Gly Glu Glu Ala Thr Thr Thr Lys Ser Gln Val Leu 200 205 210 Asp TyrLeu Ser Tyr Ala Val Phe Gln Leu Gly Asp Leu His Arg 215 220 225 Ala LeuGlu Leu Thr Arg Arg Leu Leu Ser Leu Asp Pro Ser His 230 235 240 Glu ArgAla Gly Gly Asn Leu Arg Tyr Phe Glu Gln Leu Leu Glu 245 250 255 Glu GluArg Glu Lys Thr Leu Thr Asn Gln Thr Glu Ala Glu Leu 260 265 270 Ala ThrPro Glu Gly Ile Tyr Glu Arg Pro Val Asp Tyr Leu Pro 275 280 285 Glu ArgAsp Val Tyr Glu Ser Leu Cys Arg Gly Glu Gly Val Lys 290 295 300 Leu ThrPro Arg Arg Gln Lys Arg Leu Phe Cys Arg Tyr His His 305 310 315 Gly AsnArg Ala Pro Gln Leu Leu Ile Ala Pro Phe Lys Glu Glu 320 325 330 Asp GluTrp Asp Ser Pro His Ile Val Arg Tyr Tyr Asp Val Met 335 340 345 Ser AspGlu Glu Ile Glu Arg Ile Lys Glu Ile Ala Lys Pro Lys 350 355 360 Leu AlaArg Ala Thr Val Arg Asp Pro Lys Thr Gly Val Leu Thr 365 370 375 Val AlaSer Tyr Arg Val Ser Lys Ser Ser Trp Leu Glu Glu Asp 380 385 390 Asp AspPro Val Val Ala Arg Val Asn Arg Arg Met Gln His Ile 395 400 405 Thr GlyLeu Thr Val Lys Thr Ala Glu Leu Leu Gln Val Ala Asn 410 415 420 Tyr GlyVal Gly Gly Gln Tyr Glu Pro His Phe Asp Phe Ser Arg 425 430 435 Arg ProPhe Asp Ser Gly Leu Lys Thr Glu Gly Asn Arg Leu Ala 440 445 450 Thr PheLeu Asn Tyr Met Ser Asp Val Glu Ala Gly Gly Ala Thr 455 460 465 Val PhePro Asp Leu Gly Ala Ala Ile Trp Pro Lys Lys Gly Thr 470 475 480 Ala ValPhe Trp Tyr Asn Leu Leu Arg Ser Gly Glu Gly Asp Tyr 485 490 495 Arg ThrArg His Ala Ala Cys Pro Val Leu Val Gly Cys Lys Trp 500 505 510 Val SerAsn Lys Trp Phe His Glu Arg Gly Gln Glu Phe Leu Arg 515 520 525 Pro CysGly Ser Thr Glu Val Asp 530 333 18 DNA Artificial Sequence SyntheticOligonucleotide Probe 333 ccaggcacaa tttccaga 18 334 19 DNA ArtificialSequence Synthetic Oligonucleotide Probe 334 ggacccttct gtgtgccag 19 33519 DNA Artificial Sequence Synthetic Oligonucleotide Probe 335ggtctcaaga actcctgtc 19 336 24 DNA Artificial Sequence SyntheticOligonucleotide Probe 336 acactcagca ttgcctggta cttg 24 337 45 DNAArtificial Sequence Synthetic Oligonucleotide Probe 337 gggcacatgactgacctgat ttatgcagag aaagagctgg tgcag 45 338 2789 DNA Homo Sapien 338gcagtattga gttttacttc ctcctctttt tagtggaaga cagaccataa 50 tcccagtgtgagtgaaattg attgtttcat ttattaccgt tttggctggg 100 ggttagttcc gacaccttcacagttgaaga gcaggcagaa ggagttgtga 150 agacaggaca atcttcttgg ggatgctggtcctggaagcc agcgggcctt 200 gctctgtctt tggcctcatt gaccccaggt tctctggttaaaactgaaag 250 cctactactg gcctggtgcc catcaatcca ttgatccttg aggctgtgcc300 cctggggcac ccacctggca gggcctacca ccatgcgact gagctccctg 350ttggctctgc tgcggccagc gcttcccctc atcttagggc tgtctctggg 400 gtgcagcctgagcctcctgc gggtttcctg gatccagggg gagggagaag 450 atccctgtgt cgaggctgtaggggagcgag gagggccaca gaatccagat 500 tcgagagctc ggctagacca aagtgatgaagacttcaaac cccggattgt 550 cccctactac agggacccca acaagcccta caagaaggtgctcaggactc 600 ggtacatcca gacagagctg ggctcccgtg agcggttgct ggtggctgtc650 ctgacctccc gagctacact gtccactttg gccgtggctg tgaaccgtac 700ggtggcccat cacttccctc ggttactcta cttcactggg cagcgggggg 750 cccgggctccagcagggatg caggtggtgt ctcatgggga tgagcggccc 800 gcctggctca tgtcagagaccctgcgccac cttcacacac actttggggc 850 cgactacgac tggttcttca tcatgcaggatgacacatat gtgcaggccc 900 cccgcctggc agcccttgct ggccacctca gcatcaaccaagacctgtac 950 ttaggccggg cagaggagtt cattggcgca ggcgagcagg cccggtactg1000 tcatgggggc tttggctacc tgttgtcacg gagtctcctg cttcgtctgc 1050ggccacatct ggatggctgc cgaggagaca ttctcagtgc ccgtcctgac 1100 gagtggcttggacgctgcct cattgactct ctgggcgtcg gctgtgtctc 1150 acagcaccag gggcagcagtatcgctcatt tgaactggcc aaaaataggg 1200 accctgagaa ggaagggagc tcggctttcctgagtgcctt cgccgtgcac 1250 cctgtctccg aaggtaccct catgtaccgg ctccacaaacgcttcagcgc 1300 tctggagttg gagcgggctt acagtgaaat agaacaactg caggctcaga1350 tccggaacct gaccgtgctg acccccgaag gggaggcagg gctgagctgg 1400cccgttgggc tccctgctcc tttcacacca cactctcgct ttgaggtgct 1450 gggctgggactacttcacag agcagcacac cttctcctgt gcagatgggg 1500 ctcccaagtg cccactacagggggctagca gggcggacgt gggtgatgcg 1550 ttggagactg ccctggagca gctcaatcggcgctatcagc cccgcctgcg 1600 cttccagaag cagcgactgc tcaacggcta tcggcgcttcgacccagcac 1650 ggggcatgga gtacaccctg gacctgctgt tggaatgtgt gacacagcgt1700 gggcaccggc gggccctggc tcgcagggtc agcctgctgc ggccactgag 1750ccgggtggaa atcctaccta tgccctatgt cactgaggcc acccgagtgc 1800 agctggtgctgccactcctg gtggctgaag ctgctgcagc cccggctttc 1850 ctcgaggcgt ttgcagccaatgtcctggag ccacgagaac atgcattgct 1900 caccctgttg ctggtctacg ggccacgagaaggtggccgt ggagctccag 1950 acccatttct tggggtgaag gctgcagcag cggagttagagcgacggtac 2000 cctgggacga ggctggcctg gctcgctgtg cgagcagagg ccccttccca2050 ggtgcgactc atggacgtgg tctcgaagaa gcaccctgtg gacactctct 2100tcttccttac caccgtgtgg acaaggcctg ggcccgaagt cctcaaccgc 2150 tgtcgcatgaatgccatctc tggctggcag gccttctttc cagtccattt 2200 ccaggagttc aatcctgccctgtcaccaca gagatcaccc ccagggcccc 2250 cgggggctgg ccctgacccc ccctcccctcctggtgctga cccctcccgg 2300 ggggctccta taggggggag atttgaccgg caggcttctgcggagggctg 2350 cttctacaac gctgactacc tggcggcccg agcccggctg gcaggtgaac2400 tggcaggcca ggaagaggag gaagccctgg aggggctgga ggtgatggat 2450gttttcctcc ggttctcagg gctccacctc tttcgggccg tagagccagg 2500 gctggtgcagaagttctccc tgcgagactg cagcccacgg ctcagtgaag 2550 aactctacca ccgctgccgcctcagcaacc tggaggggct agggggccgt 2600 gcccagctgg ctatggctct ctttgagcaggagcaggcca atagcactta 2650 gcccgcctgg gggccctaac ctcattacct ttcctttgtctgcctcagcc 2700 ccaggaaggg caaggcaaga tggtggacag atagagaatt gttgctgtat2750 tttttaaata tgaaaatgtt attaaacatg tcttctgcc 2789 339 772 PRT HomoSapien 339 Met Arg Leu Ser Ser Leu Leu Ala Leu Leu Arg Pro Ala Leu Pro 15 10 15 Leu Ile Leu Gly Leu Ser Leu Gly Cys Ser Leu Ser Leu Leu Arg 2025 30 Val Ser Trp Ile Gln Gly Glu Gly Glu Asp Pro Cys Val Glu Ala 35 4045 Val Gly Glu Arg Gly Gly Pro Gln Asn Pro Asp Ser Arg Ala Arg 50 55 60Leu Asp Gln Ser Asp Glu Asp Phe Lys Pro Arg Ile Val Pro Tyr 65 70 75 TyrArg Asp Pro Asn Lys Pro Tyr Lys Lys Val Leu Arg Thr Arg 80 85 90 Tyr IleGln Thr Glu Leu Gly Ser Arg Glu Arg Leu Leu Val Ala 95 100 105 Val LeuThr Ser Arg Ala Thr Leu Ser Thr Leu Ala Val Ala Val 110 115 120 Asn ArgThr Val Ala His His Phe Pro Arg Leu Leu Tyr Phe Thr 125 130 135 Gly GlnArg Gly Ala Arg Ala Pro Ala Gly Met Gln Val Val Ser 140 145 150 His GlyAsp Glu Arg Pro Ala Trp Leu Met Ser Glu Thr Leu Arg 155 160 165 His LeuHis Thr His Phe Gly Ala Asp Tyr Asp Trp Phe Phe Ile 170 175 180 Met GlnAsp Asp Thr Tyr Val Gln Ala Pro Arg Leu Ala Ala Leu 185 190 195 Ala GlyHis Leu Ser Ile Asn Gln Asp Leu Tyr Leu Gly Arg Ala 200 205 210 Glu GluPhe Ile Gly Ala Gly Glu Gln Ala Arg Tyr Cys His Gly 215 220 225 Gly PheGly Tyr Leu Leu Ser Arg Ser Leu Leu Leu Arg Leu Arg 230 235 240 Pro HisLeu Asp Gly Cys Arg Gly Asp Ile Leu Ser Ala Arg Pro 245 250 255 Asp GluTrp Leu Gly Arg Cys Leu Ile Asp Ser Leu Gly Val Gly 260 265 270 Cys ValSer Gln His Gln Gly Gln Gln Tyr Arg Ser Phe Glu Leu 275 280 285 Ala LysAsn Arg Asp Pro Glu Lys Glu Gly Ser Ser Ala Phe Leu 290 295 300 Ser AlaPhe Ala Val His Pro Val Ser Glu Gly Thr Leu Met Tyr 305 310 315 Arg LeuHis Lys Arg Phe Ser Ala Leu Glu Leu Glu Arg Ala Tyr 320 325 330 Ser GluIle Glu Gln Leu Gln Ala Gln Ile Arg Asn Leu Thr Val 335 340 345 Leu ThrPro Glu Gly Glu Ala Gly Leu Ser Trp Pro Val Gly Leu 350 355 360 Pro AlaPro Phe Thr Pro His Ser Arg Phe Glu Val Leu Gly Trp 365 370 375 Asp TyrPhe Thr Glu Gln His Thr Phe Ser Cys Ala Asp Gly Ala 380 385 390 Pro LysCys Pro Leu Gln Gly Ala Ser Arg Ala Asp Val Gly Asp 395 400 405 Ala LeuGlu Thr Ala Leu Glu Gln Leu Asn Arg Arg Tyr Gln Pro 410 415 420 Arg LeuArg Phe Gln Lys Gln Arg Leu Leu Asn Gly Tyr Arg Arg 425 430 435 Phe AspPro Ala Arg Gly Met Glu Tyr Thr Leu Asp Leu Leu Leu 440 445 450 Glu CysVal Thr Gln Arg Gly His Arg Arg Ala Leu Ala Arg Arg 455 460 465 Val SerLeu Leu Arg Pro Leu Ser Arg Val Glu Ile Leu Pro Met 470 475 480 Pro TyrVal Thr Glu Ala Thr Arg Val Gln Leu Val Leu Pro Leu 485 490 495 Leu ValAla Glu Ala Ala Ala Ala Pro Ala Phe Leu Glu Ala Phe 500 505 510 Ala AlaAsn Val Leu Glu Pro Arg Glu His Ala Leu Leu Thr Leu 515 520 525 Leu LeuVal Tyr Gly Pro Arg Glu Gly Gly Arg Gly Ala Pro Asp 530 535 540 Pro PheLeu Gly Val Lys Ala Ala Ala Ala Glu Leu Glu Arg Arg 545 550 555 Tyr ProGly Thr Arg Leu Ala Trp Leu Ala Val Arg Ala Glu Ala 560 565 570 Pro SerGln Val Arg Leu Met Asp Val Val Ser Lys Lys His Pro 575 580 585 Val AspThr Leu Phe Phe Leu Thr Thr Val Trp Thr Arg Pro Gly 590 595 600 Pro GluVal Leu Asn Arg Cys Arg Met Asn Ala Ile Ser Gly Trp 605 610 615 Gln AlaPhe Phe Pro Val His Phe Gln Glu Phe Asn Pro Ala Leu 620 625 630 Ser ProGln Arg Ser Pro Pro Gly Pro Pro Gly Ala Gly Pro Asp 635 640 645 Pro ProSer Pro Pro Gly Ala Asp Pro Ser Arg Gly Ala Pro Ile 650 655 660 Gly GlyArg Phe Asp Arg Gln Ala Ser Ala Glu Gly Cys Phe Tyr 665 670 675 Asn AlaAsp Tyr Leu Ala Ala Arg Ala Arg Leu Ala Gly Glu Leu 680 685 690 Ala GlyGln Glu Glu Glu Glu Ala Leu Glu Gly Leu Glu Val Met 695 700 705 Asp ValPhe Leu Arg Phe Ser Gly Leu His Leu Phe Arg Ala Val 710 715 720 Glu ProGly Leu Val Gln Lys Phe Ser Leu Arg Asp Cys Ser Pro 725 730 735 Arg LeuSer Glu Glu Leu Tyr His Arg Cys Arg Leu Ser Asn Leu 740 745 750 Glu GlyLeu Gly Gly Arg Ala Gln Leu Ala Met Ala Leu Phe Glu 755 760 765 Gln GluGln Ala Asn Ser Thr 770 340 1572 DNA Homo Sapien 340 cggagtggtgcgccaacgtg agaggaaacc cgtgcgcggc tgcgctttcc 50 tgtccccaag ccgttctagacgcgggaaaa atgctttctg aaagcagctc 100 ctttttgaag ggtgtgatgc ttggaagcattttctgtgct ttgatcacta 150 tgctaggaca cattaggatt ggtcatggaa atagaatgcaccaccatgag 200 catcatcacc tacaagctcc taacaaagaa gatatcttga aaatttcaga250 ggatgagcgc atggagctca gtaagagctt tcgagtatac tgtattatcc 300ttgtaaaacc caaagatgtg agtctttggg ctgcagtaaa ggagacttgg 350 accaaacactgtgacaaagc agagttcttc agttctgaaa atgttaaagt 400 gtttgagtca attaatatggacacaaatga catgtggtta atgatgagaa 450 aagcttacaa atacgccttt gataagtatagagaccaata caactggttc 500 ttccttgcac gccccactac gtttgctatc attgaaaacctaaagtattt 550 tttgttaaaa aaggatccat cacagccttt ctatctaggc cacactataa600 aatctggaga ccttgaatat gtgggtatgg aaggaggaat tgtcttaagt 650gtagaatcaa tgaaaagact taacagcctt ctcaatatcc cagaaaagtg 700 tcctgaacagggagggatga tttggaagat atctgaagat aaacagctag 750 cagtttgcct gaaatatgctggagtatttg cagaaaatgc agaagatgct 800 gatggaaaag atgtatttaa taccaaatctgttgggcttt ctattaaaga 850 ggcaatgact tatcacccca accaggtagt agaaggctgttgttcagata 900 tggctgttac ttttaatgga ctgactccaa atcagatgca tgtgatgatg950 tatggggtat accgccttag ggcatttggg catattttca atgatgcatt 1000ggttttctta cctccaaatg gttctgacaa tgactgagaa gtggtagaaa 1050 agcgtgaatatgatctttgt ataggacgtg tgttgtcatt atttgtagta 1100 gtaactacat atccaatacagctgtatgtt tctttttctt ttctaatttg 1150 gtggcactgg tataaccaca cattaaagtcagtagtacat ttttaaatga 1200 gggtggtttt tttctttaaa acacatgaac attgtaaatgtgttggaaag 1250 aagtgtttta agaataataa ttttgcaaat aaactattaa taaatattat1300 atgtgataaa ttctaaatta tgaacattag aaatctgtgg ggcacatatt 1350tttgctgatt ggttaaaaaa ttttaacagg tctttagcgt tctaagatat 1400 gcaaatgatatctctagttg tgaatttgtg attaaagtaa aacttttagc 1450 tgtgtgttcc ctttacttctaatactgatt tatgttctaa gcctccccaa 1500 gttccaatgg atttgccttc tcaaaatgtacaactaagca actaaagaaa 1550 attaaagtga aagttgaaaa at 1572 341 318 PRTHomo Sapien 341 Met Leu Ser Glu Ser Ser Ser Phe Leu Lys Gly Val Met LeuGly 1 5 10 15 Ser Ile Phe Cys Ala Leu Ile Thr Met Leu Gly His Ile ArgIle 20 25 30 Gly His Gly Asn Arg Met His His His Glu His His His Leu Gln35 40 45 Ala Pro Asn Lys Glu Asp Ile Leu Lys Ile Ser Glu Asp Glu Arg 5055 60 Met Glu Leu Ser Lys Ser Phe Arg Val Tyr Cys Ile Ile Leu Val 65 7075 Lys Pro Lys Asp Val Ser Leu Trp Ala Ala Val Lys Glu Thr Trp 80 85 90Thr Lys His Cys Asp Lys Ala Glu Phe Phe Ser Ser Glu Asn Val 95 100 105Lys Val Phe Glu Ser Ile Asn Met Asp Thr Asn Asp Met Trp Leu 110 115 120Met Met Arg Lys Ala Tyr Lys Tyr Ala Phe Asp Lys Tyr Arg Asp 125 130 135Gln Tyr Asn Trp Phe Phe Leu Ala Arg Pro Thr Thr Phe Ala Ile 140 145 150Ile Glu Asn Leu Lys Tyr Phe Leu Leu Lys Lys Asp Pro Ser Gln 155 160 165Pro Phe Tyr Leu Gly His Thr Ile Lys Ser Gly Asp Leu Glu Tyr 170 175 180Val Gly Met Glu Gly Gly Ile Val Leu Ser Val Glu Ser Met Lys 185 190 195Arg Leu Asn Ser Leu Leu Asn Ile Pro Glu Lys Cys Pro Glu Gln 200 205 210Gly Gly Met Ile Trp Lys Ile Ser Glu Asp Lys Gln Leu Ala Val 215 220 225Cys Leu Lys Tyr Ala Gly Val Phe Ala Glu Asn Ala Glu Asp Ala 230 235 240Asp Gly Lys Asp Val Phe Asn Thr Lys Ser Val Gly Leu Ser Ile 245 250 255Lys Glu Ala Met Thr Tyr His Pro Asn Gln Val Val Glu Gly Cys 260 265 270Cys Ser Asp Met Ala Val Thr Phe Asn Gly Leu Thr Pro Asn Gln 275 280 285Met His Val Met Met Tyr Gly Val Tyr Arg Leu Arg Ala Phe Gly 290 295 300His Ile Phe Asn Asp Ala Leu Val Phe Leu Pro Pro Asn Gly Ser 305 310 315Asp Asn Asp 342 23 DNA Artificial Sequence Synthetic OligonucleotideProbe 342 tccccaagcc gttctagacg cgg 23 343 18 DNA Artificial SequenceSynthetic Oligonucleotide Probe 343 ctggttcttc cttgcacg 18 344 28 DNAArtificial Sequence Synthetic Oligonucleotide Probe 344 gcccaaatgccctaaggcgg tatacccc 28 345 50 DNA Artificial Sequence SyntheticOligonucleotide Probe 345 gggtgtgatg cttggaagca ttttctgtgc tttgatcactatgctaggac 50 346 25 DNA Artificial Sequence Synthetic OligonucleotideProbe 346 gggatgcagg tggtgtctca tgggg 25 347 18 DNA Artificial SequenceSynthetic Oligonucleotide Probe 347 ccctcatgta ccggctcc 18 348 48 DNAArtificial Sequence Synthetic Oligonucleotide Probe 348 ggattctaatacgactcact atagggctca gaaaagcgca acagagaa 48 349 47 DNA ArtificialSequence Synthetic Oligonucleotide Probe 349 ctatgaaatt aaccctcactaaagggatgt cttccatgcc aaccttc 47 350 48 DNA Artificial SequenceSynthetic Oligonucleotide Probe 350 ggattctaat acgactcact atagggcggcgatgtccact ggggctac 48 351 48 DNA Artificial Sequence SyntheticOligonucleotide Probe 351 ctatgaaatt aaccctcact aaagggacga ggaagatgggcggatggt 48 352 47 DNA Artificial Sequence Synthetic OligonucleotideProbe 352 ggattctaat acgactcact atagggcacc cacgcgtccg gctgctt 47 353 48DNA Artificial Sequence Synthetic Oligonucleotide Probe 353 ctatgaaattaaccctcact aaagggacgg gggacaccac ggaccaga 48 354 48 DNA ArtificialSequence Synthetic Oligonucleotide Probe 354 ggattctaat acgactcactatagggcttg ctgcggtttt tgttcctg 48 355 48 DNA Artificial SequenceSynthetic Oligonucleotide Probe 355 ctatgaaatt aaccctcact aaagggagctgccgatccca ctggtatt 48 356 46 DNA Artificial Sequence SyntheticOligonucleotide Probe 356 ggattctaat acgactcact atagggcgga tcctggccggcctctg 46 357 48 DNA Artificial Sequence Synthetic Oligonucleotide Probe357 ctatgaaatt aaccctcact aaagggagcc cgggcatggt ctcagtta 48 358 47 DNAArtificial Sequence Synthetic Oligonucleotide Probe 358 ggattctaatacgactcact atagggcggg aagatggcga ggaggag 47 359 48 DNA ArtificialSequence Synthetic Oligonucleotide Probe 359 ctatgaaatt aaccctcactaaagggacca aggccacaaa cggaaatc 48 360 48 DNA Artificial SequenceSynthetic Oligonucleotide Probe 360 ggattctaat acgactcact atagggctgtgctttcattc tgccagta 48 361 48 DNA Artificial Sequence SyntheticOligonucleotide Probe 361 ctatgaaatt aaccctcact aaagggaggg tacaattaaggggtggat 48 362 47 DNA Artificial Sequence Synthetic OligonucleotideProbe 362 ggattctaat acgactcact atagggcccg cctcgctcct gctcctg 47 363 48DNA Artificial Sequence Synthetic Oligonucleotide Probe 363 ctatgaaattaaccctcact aaagggagga ttgccgcgac cctcacag 48 364 47 DNA ArtificialSequence Synthetic Oligonucleotide Probe 364 ggattctaat acgactcactatagggcccc tcctgccttc cctgtcc 47 365 48 DNA Artificial SequenceSynthetic Oligonucleotide Probe 365 ctatgaaatt aaccctcact aaagggagtggtggccgcga ttatctgc 48 366 48 DNA Artificial Sequence SyntheticOligonucleotide Probe 366 ggattctaat acgactcact atagggcgca gcgatggcagcgatgagg 48 367 47 DNA Artificial Sequence Synthetic OligonucleotideProbe 367 ctatgaaatt aaccctcact aaagggacag acggggcaga gggagtg 47 368 47DNA Artificial Sequence Synthetic Oligonucleotide Probe 368 ggattctaatacgactcact atagggccag gaggcgtgag gagaaac 47 369 48 DNA ArtificialSequence Synthetic Oligonucleotide Probe 369 ctatgaaatt aaccctcactaaagggaaag acatgtcatc gggagtgg 48 370 48 DNA Artificial SequenceSynthetic Oligonucleotide Probe 370 ggattctaat acgactcact atagggccgggtggaggtgg aacagaaa 48 371 48 DNA Artificial Sequence SyntheticOligonucleotide Probe 371 ctatgaaatt aaccctcact aaagggacac agacagagccccatacgc 48 372 47 DNA Artificial Sequence Synthetic OligonucleotideProbe 372 ggattctaat acgactcact atagggccag ggaaatccgg atgtctc 47 373 48DNA Artificial Sequence Synthetic Oligonucleotide Probe 373 ctatgaaattaaccctcact aaagggagta aggggatgcc accgagta 48 374 47 DNA ArtificialSequence Synthetic Oligonucleotide Probe 374 ggattctaat acgactcactatagggccag ctacccgcag gaggagg 47 375 48 DNA Artificial SequenceSynthetic Oligonucleotide Probe 375 ctatgaaatt aaccctcact aaagggatcccaggtgatga ggtccaga 48 376 997 DNA Homo Sapien 376 cccacgcgtc cgatcttaccaacaaaacac tcctgaggag aaagaaagag 50 agggagggag agaaaaagag agagagagaaacaaaaaacc aaagagagag 100 aaaaaatgaa ttcatctaaa tcatctgaaa cacaatgcacagagagagga 150 tgcttctctt cccaaatgtt cttatggact gttgctggga tccccatcct200 atttctcagt gcctgtttca tcaccagatg tgttgtgaca tttcgcatct 250ttcaaacctg tgatgagaaa aagtttcagc tacctgagaa tttcacagag 300 ctctcctgctacaattatgg atcaggttca gtcaagaatt gttgtccatt 350 gaactgggaa tattttcaatccagctgcta cttcttttct actgacacca 400 tttcctgggc gttaagttta aagaactgctcagccatggg ggctcacctg 450 gtggttatca actcacagga ggagcaggaa ttcctttcctacaagaaacc 500 taaaatgaga gagtttttta ttggactgtc agaccaggtt gtcgagggtc550 agtggcaatg ggtggacggc acacctttga caaagtctct gagcttctgg 600gatgtagggg agcccaacaa catagctacc ctggaggact gtgccaccat 650 gagagactcttcaaacccaa ggcaaaattg gaatgatgta acctgtttcc 700 tcaattattt tcggatttgtgaaatggtag gaataaatcc tttgaacaaa 750 ggaaaatctc tttaagaaca gaaggcacaactcaaatgtg taaagaagga 800 agagcaagaa catggccaca cccaccgccc cacacgagaaatttgtgcgc 850 tgaacttcaa aggacttcat aagtatttgt tactctgata caaataaaaa900 taagtagttt taaatgttaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 950aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaa 997 377 219 PRT HomoSapien 377 Met Asn Ser Ser Lys Ser Ser Glu Thr Gln Cys Thr Glu Arg Gly 15 10 15 Cys Phe Ser Ser Gln Met Phe Leu Trp Thr Val Ala Gly Ile Pro 2025 30 Ile Leu Phe Leu Ser Ala Cys Phe Ile Thr Arg Cys Val Val Thr 35 4045 Phe Arg Ile Phe Gln Thr Cys Asp Glu Lys Lys Phe Gln Leu Pro 50 55 60Glu Asn Phe Thr Glu Leu Ser Cys Tyr Asn Tyr Gly Ser Gly Ser 65 70 75 ValLys Asn Cys Cys Pro Leu Asn Trp Glu Tyr Phe Gln Ser Ser 80 85 90 Cys TyrPhe Phe Ser Thr Asp Thr Ile Ser Trp Ala Leu Ser Leu 95 100 105 Lys AsnCys Ser Ala Met Gly Ala His Leu Val Val Ile Asn Ser 110 115 120 Gln GluGlu Gln Glu Phe Leu Ser Tyr Lys Lys Pro Lys Met Arg 125 130 135 Glu PhePhe Ile Gly Leu Ser Asp Gln Val Val Glu Gly Gln Trp 140 145 150 Gln TrpVal Asp Gly Thr Pro Leu Thr Lys Ser Leu Ser Phe Trp 155 160 165 Asp ValGly Glu Pro Asn Asn Ile Ala Thr Leu Glu Asp Cys Ala 170 175 180 Thr MetArg Asp Ser Ser Asn Pro Arg Gln Asn Trp Asn Asp Val 185 190 195 Thr CysPhe Leu Asn Tyr Phe Arg Ile Cys Glu Met Val Gly Ile 200 205 210 Asn ProLeu Asn Lys Gly Lys Ser Leu 215 378 21 DNA Artificial Sequence SyntheticOligonucleotide Probe 378 ttcagcttct gggatgtagg g 21 379 24 DNAArtificial Sequence Synthetic Oligonucleotide Probe 379 tattcctaccatttcacaaa tccg 24 380 49 DNA Artificial Sequence Syntheticoligonucleotide probe 380 ggaggactgt gccaccatga gagactcttc aaacccaaggcaaaattgg 49 381 26 DNA Artificial Sequence Synthetic oligonucleotideprobe 381 gcagattttg aggacagcca cctcca 26 382 18 DNA Artificial SequenceSynthetic oligonucleotide probe 382 ggccttgcag acaaccgt 18 383 21 DNAArtificial Sequence Synthetic oligonucleotide probe 383 cagactgagggagatccgag a 21 384 20 DNA Artificial Sequence Synthetic oligonucleotideprobe 384 cagctgccct tccccaacca 20 385 18 DNA Artificial SequenceSynthetic oligonucleotide probe 385 catcaagcgc ctctacca 18 386 21 DNAArtificial Sequence Synthetic oligonucleotide probe 386 cacaaactcgaactgcttct g 21 387 18 DNA Artificial Sequence Synthetic oligonucleotideprobe 387 gggccatcac agctccct 18 388 22 DNA Artificial SequenceSynthetic oligonucleotide probe 388 gggatgtggt gaacacagaa ca 22 389 22DNA Artificial Sequence Synthetic oligonucleotide probe 389 tgccagctgcatgctgccag tt 22 390 20 DNA Artificial Sequence Syntheticoligonucleotide probe 390 cagaaggatg tcccgtggaa 20 391 17 DNA ArtificialSequence Synthetic oligonucleotide probe 391 gccgctgtcc actgcag 17 39221 DNA Artificial Sequence Synthetic oligonucleotide probe 392gacggcatcc tcagggccac a 21 393 20 DNA Artificial Sequence Syntheticoligonucleotide probe 393 atgtcctcca tgcccacgcg 20 394 20 DNA ArtificialSequence Synthetic oligonucleotide probe 394 gagtgcgaca tcgagagctt 20395 18 DNA Artificial Sequence Synthetic oligonucleotide probe 395ccgcagcctc agtgatga 18 396 21 DNA Artificial Sequence Syntheticoligonucleotide probe 396 gaagagcaca gctgcagatc c 21 397 22 DNAArtificial Sequence Synthetic oligonucleotide probe 397 gaggtgtcctggctttggta gt 22 398 20 DNA Artificial Sequence Syntheticoligonucleotide probe 398 cctctggcgc ccccactcaa 20 399 18 DNA ArtificialSequence Synthetic oligonucleotide probe 399 ccaggagagc tggcgatg 18 40023 DNA Artificial Sequence Synthetic oligonucleotide probe 400gcaaattcag ggctcactag aga 23 401 29 DNA Artificial Sequence Syntheticoligonucleotide probe 401 cacagagcat ttgtccatca gcagttcag 29 402 22 DNAArtificial Sequence Synthetic oligonucleotide probe 402 ggcagagacttccagtcact ga 22 403 22 DNA Artificial Sequence Syntheticoligonucleotide probe 403 gccaagggtg gtgttagata gg 22 404 24 DNAArtificial Sequence Synthetic oligonucleotide probe 404 caggcccccttgatctgtac ccca 24 405 23 DNA Artificial Sequence Syntheticoligonucleotide probe 405 gggacgtgct tctacaagaa cag 23 406 26 DNAArtificial Sequence Synthetic oligonucleotide probe 406 caggcttacaatgttatgat cagaca 26 407 31 DNA Artificial Sequence Syntheticoligonucleotide probe 407 tattcagagt tttccattgg cagtgccagt t 31 408 21DNA Artificial Sequence Synthetic oligonucleotide probe 408 tctacatcagcctctctgcg c 21 409 23 DNA Artificial Sequence Synthetic oligonucleotideprobe 409 cgatcttctc cacccaggag cgg 23 410 18 DNA Artificial SequenceSynthetic oligonucleotide probe 410 gccaggcctc acattcgt 18 411 23 DNAArtificial Sequence Synthetic oligonucleotide probe 411 ctccctgaatggcagcctga gca 23 412 24 DNA Artificial Sequence Syntheticoligonucleotide probe 412 aggtgtttat taagggccta cgct 24 413 19 DNAArtificial Sequence Synthetic oligonucleotide probe 413 cagagcagagggtgccttg 19 414 21 DNA Artificial Sequence Synthetic oligonucleotideprobe 414 tggcggagtc ccctcttggc t 21 415 22 DNA Artificial SequenceSynthetic oligonucleotide probe 415 ccctgtttcc ctatgcatca ct 22 416 21DNA Artificial Sequence Synthetic oligonucleotide probe 416 tcaacccctgaccctttcct a 21 417 24 DNA Artificial Sequence Synthetic oligonucleotideprobe 417 ggcaggggac aagccatctc tcct 24 418 20 DNA Artificial SequenceSynthetic oligonucleotide probe 418 gggactgaac tgccagcttc 20 419 22 DNAArtificial Sequence Synthetic oligonucleotide probe 419 gggccctaacctcattacct tt 22 420 23 DNA Artificial Sequence Syntheticoligonucleotide probe 420 tgtctgcctc agccccagga agg 23 421 21 DNAArtificial Sequence Synthetic oligonucleotide probe 421 tctgtccaccatcttgcctt g 21 422 3554 DNA Homo Sapien 422 gggactacaa gccgcgccgcgctgccgctg gcccctcagc aaccctcgac 50 atggcgctga ggcggccacc gcgactccggctctgcgctc ggctgcctga 100 cttcttcctg ctgctgcttt tcaggggctg cctgataggggctgtaaatc 150 tcaaatccag caatcgaacc ccagtggtac aggaatttga aagtgtggaa200 ctgtcttgca tcattacgga ttcgcagaca agtgacccca ggatcgagtg 250gaagaaaatt caagatgaac aaaccacata tgtgtttttt gacaacaaaa 300 ttcagggagacttggcgggt cgtgcagaaa tactggggaa gacatccctg 350 aagatctgga atgtgacacggagagactca gccctttatc gctgtgaggt 400 cgttgctcga aatgaccgca aggaaattgatgagattgtg atcgagttaa 450 ctgtgcaagt gaagccagtg acccctgtct gtagagtgccgaaggctgta 500 ccagtaggca agatggcaac actgcactgc caggagagtg agggccaccc550 ccggcctcac tacagctggt atcgcaatga tgtaccactg cccacggatt 600ccagagccaa tcccagattt cgcaattctt ctttccactt aaactctgaa 650 acaggcactttggtgttcac tgctgttcac aaggacgact ctgggcagta 700 ctactgcatt gcttccaatgacgcaggctc agccaggtgt gaggagcagg 750 agatggaagt ctatgacctg aacattggcggaattattgg gggggttctg 800 gttgtccttg ctgtactggc cctgatcacg ttgggcatctgctgtgcata 850 cagacgtggc tacttcatca acaataaaca ggatggagaa agttacaaga900 acccagggaa accagatgga gttaactaca tccgcactga cgaggagggc 950gacttcagac acaagtcatc gtttgtgatc tgagacccgc ggtgtggctg 1000 agagcgcacagagcgcacgt gcacatacct ctgctagaaa ctcctgtcaa 1050 ggcagcgaga gctgatgcactcggacagag ctagacactc attcagaagc 1100 ttttcgtttt ggccaaagtt gaccactactcttcttactc taacaagcca 1150 catgaataga agaattttcc tcaagatgga cccggtaaatataaccacaa 1200 ggaagcgaaa ctgggtgcgt tcactgagtt gggttcctaa tctgtttctg1250 gcctgattcc cgcatgagta ttagggtgat cttaaagagt ttgctcacgt 1300aaacgcccgt gctgggccct gtgaagccag catgttcacc actggtcgtt 1350 cagcagccacgacagcacca tgtgagatgg cgaggtggct ggacagcacc 1400 agcagcgcat cccggcgggaacccagaaaa ggcttcttac acagcagcct 1450 tacttcatcg gcccacagac accaccgcagtttcttctta aaggctctgc 1500 tgatcggtgt tgcagtgtcc attgtggaga agctttttggatcagcattt 1550 tgtaaaaaca accaaaatca ggaaggtaaa ttggttgctg gaagagggat1600 cttgcctgag gaaccctgct tgtccaacag ggtgtcagga tttaaggaaa 1650accttcgtct taggctaagt ctgaaatggt actgaaatat gcttttctat 1700 gggtcttgtttattttataa aattttacat ctaaattttt gctaaggatg 1750 tattttgatt attgaaaagaaaatttctat ttaaactgta aatatattgt 1800 catacaatgt taaataacct atttttttaaaaaagttcaa cttaaggtag 1850 aagttccaag ctactagtgt taaattggaa aatatcaataattaagagta 1900 ttttacccaa ggaatcctct catggaagtt tactgtgatg ttccttttct1950 cacacaagtt ttagcctttt tcacaaggga actcatactg tctacacatc 2000agaccatagt tgcttaggaa acctttaaaa attccagtta agcaatgttg 2050 aaatcagtttgcatctcttc aaaagaaacc tctcaggtta gctttgaact 2100 gcctcttcct gagatgactaggacagtctg tacccagagg ccacccagaa 2150 gccctcagat gtacatacac agatgccagtcagctcctgg ggttgcgcca 2200 ggcgcccccg ctctagctca ctgttgcctc gctgtctgccaggaggccct 2250 gccatccttg ggccctggca gtggctgtgt cccagtgagc tttactcacg2300 tggcccttgc ttcatccagc acagctctca ggtgggcact gcagggacac 2350tggtgtcttc catgtagcgt cccagctttg ggctcctgta acagacctct 2400 ttttggttatggatggctca caaaataggg cccccaatgc tatttttttt 2450 ttttaagttt gtttaattatttgttaagat tgtctaaggc caaaggcaat 2500 tgcgaaatca agtctgtcaa gtacaataacatttttaaaa gaaaatggat 2550 cccactgttc ctctttgcca cagagaaagc acccagacgccacaggctct 2600 gtcgcatttc aaaacaaacc atgatggagt ggcggccagt ccagcctttt2650 aaagaacgtc aggtggagca gccaggtgaa aggcctggcg gggaggaaag 2700tgaaacgcct gaatcaaaag cagttttcta attttgactt taaatttttc 2750 atccgccggagacactgctc ccatttgtgg ggggacatta gcaacatcac 2800 tcagaagcct gtgttcttcaagagcaggtg ttctcagcct cacatgccct 2850 gccgtgctgg actcaggact gaagtgctgtaaagcaagga gctgctgaga 2900 aggagcactc cactgtgtgc ctggagaatg gctctcactactcaccttgt 2950 ctttcagctt ccagtgtctt gggtttttta tactttgaca gctttttttt3000 aattgcatac atgagactgt gttgactttt tttagttatg tgaaacactt 3050tgccgcaggc cgcctggcag aggcaggaaa tgctccagca gtggctcagt 3100 gctccctggtgtctgctgca tggcatcctg gatgcttagc atgcaagttc 3150 cctccatcat tgccaccttggtagagaggg atggctcccc accctcagcg 3200 ttggggattc acgctccagc ctccttcttggttgtcatag tgatagggta 3250 gccttattgc cccctcttct tataccctaa aaccttctacactagtgcca 3300 tgggaaccag gtctgaaaaa gtagagagaa gtgaaagtag agtctgggaa3350 gtagctgcct ataactgaga ctagacggaa aaggaatact cgtgtatttt 3400aagatatgaa tgtgactcaa gactcgaggc cgatacgagg ctgtgattct 3450 gcctttggatggatgttgct gtacacagat gctacagact tgtactaaca 3500 caccgtaatt tggcatttgtttaacctcat ttataaaagc ttcaaaaaaa 3550 ccca 3554 423 310 PRT Homo Sapien423 Met Ala Leu Arg Arg Pro Pro Arg Leu Arg Leu Cys Ala Arg Leu 1 5 1015 Pro Asp Phe Phe Leu Leu Leu Leu Phe Arg Gly Cys Leu Ile Gly 20 25 30Ala Val Asn Leu Lys Ser Ser Asn Arg Thr Pro Val Val Gln Glu 35 40 45 PheGlu Ser Val Glu Leu Ser Cys Ile Ile Thr Asp Ser Gln Thr 50 55 60 Ser AspPro Arg Ile Glu Trp Lys Lys Ile Gln Asp Glu Gln Thr 65 70 75 Thr Tyr ValPhe Phe Asp Asn Lys Ile Gln Gly Asp Leu Ala Gly 80 85 90 Arg Ala Glu IleLeu Gly Lys Thr Ser Leu Lys Ile Trp Asn Val 95 100 105 Thr Arg Arg AspSer Ala Leu Tyr Arg Cys Glu Val Val Ala Arg 110 115 120 Asn Asp Arg LysGlu Ile Asp Glu Ile Val Ile Glu Leu Thr Val 125 130 135 Gln Val Lys ProVal Thr Pro Val Cys Arg Val Pro Lys Ala Val 140 145 150 Pro Val Gly LysMet Ala Thr Leu His Cys Gln Glu Ser Glu Gly 155 160 165 His Pro Arg ProHis Tyr Ser Trp Tyr Arg Asn Asp Val Pro Leu 170 175 180 Pro Thr Asp SerArg Ala Asn Pro Arg Phe Arg Asn Ser Ser Phe 185 190 195 His Leu Asn SerGlu Thr Gly Thr Leu Val Phe Thr Ala Val His 200 205 210 Lys Asp Asp SerGly Gln Tyr Tyr Cys Ile Ala Ser Asn Asp Ala 215 220 225 Gly Ser Ala ArgCys Glu Glu Gln Glu Met Glu Val Tyr Asp Leu 230 235 240 Asn Ile Gly GlyIle Ile Gly Gly Val Leu Val Val Leu Ala Val 245 250 255 Leu Ala Leu IleThr Leu Gly Ile Cys Cys Ala Tyr Arg Arg Gly 260 265 270 Tyr Phe Ile AsnAsn Lys Gln Asp Gly Glu Ser Tyr Lys Asn Pro 275 280 285 Gly Lys Pro AspGly Val Asn Tyr Ile Arg Thr Asp Glu Glu Gly 290 295 300 Asp Phe Arg HisLys Ser Ser Phe Val Ile 305 310

What is claimed is:
 1. An isolated nucleic acid comprising: (a) a nucleic acid sequence encoding the polypeptide of SEQ ID NO: 148; (b) a nucleic acid sequence encoding the polypeptide of SEQ ID NO: 148, lacking its associated signal peptide; (c) the nucleic acid sequence of SEQ ID NO: 147; or (d) the full-length coding sequence of the nucleic acid sequence of SEQ ID NO:
 147. 2. The isolated nucleic acid of claim 1 comprising a nucleic acid sequence encoding the polypeptide of SEQ ID NO:
 148. 3. The isolated nucleic acid of claim 1 comprising a nucleic acid sequence encoding the polypeptide of SEQ ID NO: 148, lacking its associated signal peptide.
 4. The isolated nucleic acid of claim 1 comprising the nucleic acid sequence of SEQ ID NO:
 147. 5. The isolated nucleic acid of claim 1 comprising the full-length coding sequence of the nucleic acid sequence of SEQ ID NO:
 147. 6. A vector comprising the nucleic acid of claim
 1. 7. The vector of claim 6, wherein said nucleic acid is operably linked to control sequences recognized by a host cell transformed with the vector.
 8. A host cell comprising the vector of claim
 6. 9. The host cell of claim 8, wherein said cell is a CHO cell, an E. coli or a yeast cell. 